Compounds, pharmaceutical compositions and uses thereof

ABSTRACT

The present invention relates to compounds of general formula I, 
                         
wherein the groups R 1 , R 2 , and A are as defined in the application, which have valuable pharmacological properties, and in particular bind to the GPR119 receptor and modulate its activity.

FIELD OF THE INVENTION

The present invention relates to new compounds of formula I

wherein the groups R¹, R², and A are defined as hereinafter, toprocesses for preparing such compounds, to pharmaceutical compositions,to their use as modulators of the G-protein-coupled receptor GPR119, tomethods for their therapeutic use, in particular in diseases andconditions mediated by the modulation of the G-protein-coupled receptorGPR119, and to pharmaceutical compositions comprising them.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a serious metabolic disease which affects more than100 million people worldwide. In the USA there are more than 12 milliondiabetics with 600,000 new cases diagnosed every year. The prevalence ofdiabetes mellitus is increasing, resulting in a high frequency ofcomplications and a substantial impairment of quality of life and lifeexpectancy. Because of diabetes-associated microvascular complications,in the industrialised countries type 2 diabetes is currently the mostcommon cause of adult-onset loss of vision, renal insufficiency andamputations. In addition, type 2 diabetes is associated with a two- tofive-fold increase in the risk of cardiovascular disease.

The UKPDS study (United Kingdom Prospective Diabetes Study) showed thatintensive treatment with common therapeutic agents, e.g. metformin,sulphonylureas or insulin, results in only a limited improvement inglycaemic control (difference in the HbA1c value ˜0.9%). Moreover,glycaemic control deteriorated considerably over time even in patientsin the intensive treatment group, and this was put down to adeterioration in beta cell function. Diabetes is also a major cause ofdamage to the retina at the back of the eye and increases the risk ofcataract and glaucoma. Finally, diabetes is associated with nervedamage, particularly in legs and feet, which affects the patient'sability to feel pain and contributes to serious infections. All in all,complications of diabetes are one of the major causes of deathworldwide.

Adiposity (obesity) is the result of an imbalance between calorie intakeand energy consumption. It correlates to a high degree with insulinresistance and diabetes. However, the molecular mechanisms that areinvolved in obesity/diabetes syndromes are not yet clear. At an earlystage of the development of obesity, an increased insulin secretionbalances out the insulin resistance and protects the patient fromhyperglycaemia. However, after a time, the beta cell function worsensand non-insulin-dependent diabetes develops in about 20% of the obesepopulation. Obesity has thus become a critical risk factor for diabetes,but the factors that predispose one group of patients to a pathologicalchange in insulin secretion as a response to the accumulation of fat arecurrently unknown. Obesity also significantly increases the risk of thedevelopment of cardiovascular disease. Diabetes is also implicated inthe formation of kidney complaints, eye complaints and problems of thenervous system. Kidney disease, also known as nephropathy, sets in whenthe filtering mechanism of the kidneys is disrupted and proteins escapeinto the urine in excessive amounts and finally the kidney fails.Therefore there is a medical need for medicaments for preventing and/ortreating metabolic disorders (particularly diabetes, predominantly type2 diabetes) and the complications thereof. In particular there is a needfor medicaments with good activity in terms of glycaemic control,disease-modifying properties and reducing cardiovascular morbidity andmortality, and which also have a better safety profile.

Dyslipidemia is a disorder of lipoprotein metabolism, includinglipoprotein overproduction or deficiency. Dyslipidemias may bemanifested by elevation of the total cholesterol, LDL cholesterol andtriglyceride and free fatty acid concentrations, and a decrease inhigh-density lipoprotein (HDL) cholesterol concentration in the blood.Dyslipidemia occurs often in situations including diabetes, a commoncause of lipidemia. For adults with diabetes, it has been recommendedthat the levels of LDL, HDL, and total cholesterol, and triglyceride bemeasured every year. Optimal LDL cholesterol levels for adults withdiabetes are less than 100 mg/dL (2.60 mmol/L), optimal HDL cholesterollevels are equal to or greater than 40 mg/dL (1.02 mmol/L), anddesirable triglyceride levels are less than 150 mg/dL (1.7 mmol/L).

GPR119 is a G-protein coupled receptor (also known as GPCR2, RUP3,SNORF25 or GDIR) which is expressed predominantly in the beta cells ofthe pancreas and in the K- and L-cells of the intestine. The GPR119receptor and isoforms have been identified in mammalian speciesincluding human, rat, mouse, hamster, chimpanzee, rhesus monkey, cattleand dog. The expression of GPR119 in the pancreas and particularly inthe pancreatic β-cells led to the hypothesis that the GPR119 receptorcould have effects upon insulin secretion. Activation of the receptorstimulates the cAMP signal pathway, increasing the intracellular levelsof cAMP in these cells. This will lead to an improved diabetic situationby a dual action of such a compound: stimulation of cAMP in the betacell occurs directly via activation of GPR119 in these cells andfurthermore indirectly via stimulation of the release of neuroendocrinepeptides like GIP and GLP-1 and PYY from the gut. The release of thesepeptides may have also additional beneficial effects, e.g. on foodintake, gastric emptying and other yet unknown functions. Also, a GPR119agonist can be expected to bring about an improvement in the beta cellfunction and the beta cell mass. In fact, activation of GPR119stimulates insulin secretion in-vitro and in-vivo (in rodents) in aglucose-dependent manner. The discovery of two endogenous ligands,lysophospha-tidylcholine (LPC) and oleoylethanolamide (OEA) as well asmore potent GPR119 agonists have led to the characterization of GPR119as both an insulin and incretin (GLP-1 and GIP) secretagogue receptorcapable of lowering plasma glucose and thereby facilitating glycemiccontrol without the risk of hypoglycemia (Biochem. Biophys. Res. Comm.2005, 744-751; Cell Metabolism 2006, 167-175; Endocrinolgy 2007,2601-9). It has recently been shown that GPR119 agonists effectivelylower the blood glucose levels in diabetic rodents without the risk ofhypoglycaemia. GPR119 knockout animals have shown that both insulin andincretin secretion induced by GPR119 agonists are dependent upon GPR119receptor. In addition, it has been shown that GPR119 agonists decreasefood intake resulting in weight loss in Sprague Dawley rats. Thereforethe GPR119 agonists may be expected to have a therapeutic benefit inmetabolic diseases. Examples of such diseases include type 1 diabetes,type 2 diabetes, insufficient glucose tolerance, insulin resistance,hyperglycaemia, hyperlipidaemia, hypercholesterolaemia, dyslipidaemia,syndrome X, metabolic syndrome, obesity, high blood pressure, chronicsystemic inflammation, retinopathy, neuropathy, nephropathy,atherosclerosis, endothelial dysfunction and bone-related diseases (suchas osteoporosis, rheumatoid arthritis or osteoarthritis). For comparisonand additional information also see

-   1. Dhayal, S., Morgan, N. G. The significance of GPR119 agonists as    a future treatment for type 2 diabetes. Drug News Perspect. 2010,    23(7), 418-24.-   2. Yoshida, S., Tanaka, H., Oshima, H., Yamazaki, T., Yonetoku, Y.,    Ohishi, T., Matsui, T., Shibasaki, M. AS1907417, a novel GPR119    agonist, as an insulinotropic and β-cell preservative agent for the    treatment of type 2 diabetes. Biochem Biophys Res Commun. 2010,    400(4), 745-51.-   3. Jones, R. M., Leonard, J. N., Buzard, D. J., Lehman, J. GPR119    agonists for the treatment of type 2 diabetes. Expert Opinion on    Therapeutic Patents 2009, Vol. 19, No. 10: 1339-1359.

AIM OF THE PRESENT INVENTION

The aim of the present invention is to provide new compounds, inparticular new furo[2,3-c]pyridine derivatives, which are active withregard to the G-protein-coupled receptor GPR119.

Another aim of the present invention is to provide new compounds, inparticular new furo[2,3-c]pyridine derivatives, which are agonists ofthe G-protein-coupled receptor GPR119.

A further aim of the present invention is to provide new compounds, inparticular new furo[2,3-c]pyridine derivatives, which have an activatingeffect on the G-protein-coupled receptor GPR119 in vitro and/or in vivoand possess suitable pharmacological and pharmacokinetic properties touse them as medicaments.

A further aim of the present invention is to provide effective GPR119agonists, in particular for the treatment of metabolic disorders, forexample diabetes, dyslipidemia and/or obesity.

A further aim of the present invention is to provide methods fortreating a disease or condition mediated by the activation of theG-protein-coupled receptor GPR119 in a patient.

A further aim of the present invention is to provide a pharmaceuticalcomposition comprising at least one compound according to the invention.

A further aim of the present invention is to provide a combination of atleast one compound according to the invention with one or moreadditional therapeutic agents.

A further aim of the present invention is to provide methods for thesynthesis of the new compounds, in particular furo[2,3-c]pyridinederivatives.

A further aim of the present invention is to provide starting and/orintermediate compounds suitable in methods for the synthesis of the newcompounds.

Further aims of the present invention become apparent to those skilledin the art by the description hereinbefore and in the following and bythe examples.

OBJECT OF THE INVENTION

It has now been found that the compounds according to the inventiondescribed in more detail hereinafter have surprising and particularlyadvantageous properties, and in particular as GPR119 agonists.

In a first aspect the invention thus relates to a compound of formula I

wherein

-   R¹ is selected from the group R¹-G1 consisting of a 5- or 6-membered    heteroaromatic ring which contains 1, 2, or 3 heteroatoms    independently of each other selected from N, O, and S, and which may    be optionally substituted with a group R^(c) and/or one or more    substituents independently selected from L^(A); and    -   a group —C(═O)—O—R^(a), wherein R^(a) denotes C₁₋₆-alkyl        optionally mono- or polysubstituted with fluorine; or        C₃₋₆-cycloalkyl optionally mono- or polysubstituted with        fluorine and optionally substituted with a group selected from        CH₃, CF₃, and CHF₂; and    -   a group —CH₂—R^(b), wherein R^(b) denotes C₁₋₆-alkyl optionally        mono- or polysubstituted with fluorine; or C₃₋₆-cycloalkyl        optionally mono- or polysubstituted with fluorine and optionally        substituted with a group selected from CH₃, CF₃, and CHF₂;-   R² is selected from the group R²-G1 consisting of H and C₁₋₃-alkyl;    and-   A is selected from the group A-G1 consisting of    1,2,3,6-tetrahydropyridin-4-yl and piperazin-1-yl, each of which    substituted at the N with a C₁₋₄-alkyl-S(═O)₂— group; and    -   a phenyl ring and a 5- or 6-membered heteroaromatic ring which        contains 1, 2 or 3 heteroatoms independently of each other        selected from N, O and S, each of which may be substituted with        a group T and may be optionally substituted with one or more        substituents independently selected from L^(A);-   T is selected from the group T-G1 consisting of F, Cl, Br, I, CN,    OH, NO₂, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl,    C₁₋₆-alkyl-O—, C₃₋₆-cycloalkyl-O—, C₁₋₆-alkyl-S—, HO—C(═O)—,    C₁₋₆-alkyl-O—C(═O)—, C₁₋₄-alkyl-C(═O)—, C₃₋₆-cycloalkyl-C(═O)—,    C₁₋₄-alkyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—, R^(NT1)R^(NT2)N—,    R^(NT1)R^(NT2)N—C(═O)—, R^(NT1)R^(NT2)N—S(═O)₂—,    R^(NT1)R^(NT2)N—C(═O)—(R^(N))N—, heterocyclyl, heterocyclyl-O—,    aryl, aryl-O—, heteroaryl and heteroaryl-O—,    -   wherein each alkyl, alkenyl, alkynyl, and cycloalkyl group may        be optionally substituted with one or more substituents        independently of each other selected from F, Cl, CN, OH,        C₁₋₃-alkyl, C₃₋₆-cycloalkyl, C₁₋₃alkyl-O—, R^(NT1)R^(NT2)N—,        R^(NT1)R^(NT2)N—C(═O)—, C₁₋₄-alkyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—,        R^(NT1)R^(NT2)N—S(═O)₂—, aryl, heteroaryl, and heterocyclyl, and    -   wherein aryl denotes phenyl or naphthyl, and    -   wherein heteroaryl is a 5- or 6-membered aromatic ring which        contains 1, 2, 3 or 4 heteroatoms independently of each other        selected from N, O and S, wherein the H-atom in one or more NH        groups may be optionally replaced by R^(N); and    -   wherein heterocyclyl is a 4- to 7-membered unsaturated or        saturated other are replaced by NR^(N), O, —C(═O)—, S, —S(═O)—        or —S(═O)₂—, and/or in which a —CH-group is replaced by N; and    -   wherein each aryl, heteroaryl or heterocyclyl group may be        optionally substituted with one or more substituents        independently of each other selected from L^(A);-   R^(N) independently of each other is selected from the group    R^(N)-G1 consisting of H, C₁₋₄-alkyl, C₁₋₄-alkyl-C(═O)—, and    C₁₋₄-alkyl-S(═O)₂—;-   R^(NT1) is selected from the group R^(NT1)-G1 consisting of H,    C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkyl-C(═O)—, C₁₋₆-alkyl-S(═O)₂—,    heterocyclyl, aryl and heteroaryl,    -   wherein each alkyl and cylcoalkyl group may be optionally        substituted with one or more substituents independently of each        other selected from the group consisting of F, OH, CN,        C₁₋₄-alkyl, C₁₋₄-alkyl-O—, R^(N) ₂N—, C₁₋₄-alkyl-S(═O)₂—,        C₃₋₆-cycloalkyl, heterocyclyl, phenyl and heteroaryl; and    -   wherein heterocyclyl may be optionally substituted with one or        more substituents independently of each other selected from F,        C₁₋₄-alkyl, R^(N) ₂N—, OH and C₁₋₄-alkyl-O—; and    -   wherein heterocyclyl is a C₄₋₇-cycloalkyl ring in which 1 or 2        —CH₂-groups independently of each other are replaced by NR^(N),        O, C(═O), S, S(═O) or S(═O)₂; and    -   wherein aryl is phenyl or naphthyl; and    -   wherein heteroaryl is a 5- or 6-membered aromatic ring which        contains 1, 2 or 3 heteroatoms independently of each other        selected from N, O and S, wherein the H-atom in one or more NH        groups may be optionally replaced by R^(N); and    -   wherein aryl and heteroaryl may be optionally substituted with        one or more substituents L^(A); and-   R^(NT2) is selected from the group R^(NT2)-G1 consisting of H and    C₁₋₆-alkyl; or-   R^(NT1) and R^(NT2) are linked to form one group selected from the    group R^(NT1)R^(NT2)-G1 consisting of a C₃₋₅-alkylene group, wherein    1 or 2 —CH₂-groups independently of each other are replaced by    NR^(N), O, C(═O), S, S(═O) or S(═O)₂; and which may be optionally    substituted with one or more substituents independently of each    other selected from F, C₁₋₄-alkyl, (R^(N))₂N—, OH and C₁₋₄-alkyl-O—;-   L^(A) is selected from the group L^(A)-G1 consisting of F, Cl, Br,    CN, OH, NO₂, C₁₋₄-alkyl, C₁₋₄-alkyl-O—, (R^(N))₂N—C(═O)—,    (R^(N))₂N—, and C₁₋₄-alkyl-S(═O)₂—, wherein each alkyl group may be    optionally substituted with one or more substituents independently    of each other selected from F, Cl, CN, OH and C₁₋₃-alkyl-O—; and-   R^(C) is selected from the group R^(C)-G1 consisting of F, Cl, Br,    I, CN, OH, NO₂, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl,    C₃₋₆-cycloalkyl, C₁₋₆-alkyl-O—, C₃₋₆-cycloalkyl-O—, C₁₋₆-alkyl-S—,    HO—C(═O)—, C₁₋₆-alkyl-O—C(═O)—, C₁₋₄-alkyl-C(═O)—,    C₃₋₆-cycloalkyl-C(═O)—, C₁₋₄-alkyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—,    R^(NT1)R^(NT2)N—, R^(NT1)R^(NT2)N—C(═O)—, R^(NT1)R^(NT2)N—S(═O)₂—,    R^(NT1)R^(NT2)N—C(═O)—(R^(N))N—, heterocyclyl, heterocyclyl-O—,    aryl, aryl-O—, heteroaryl and heteroaryl-O—,    -   wherein each alkyl, alkenyl, alkynyl, and cycloalkyl group may        be optionally substituted with one or more substituents        independently of each other selected from F, Cl, CN, OH,        C₁₋₃-alkyl, C₃₋₆-cycloalkyl, C₁₋₃-alkyl-O—, R^(NT1)R^(NT2)N—,        R^(NT1)R^(NT2)N—C(═O)—, C₁₋₄-alkyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—,        R^(NT1)R^(NT2)N—S(═O)₂—, aryl, heteroaryl, and heterocyclyl, and    -   wherein aryl denotes phenyl or naphthyl, and    -   wherein heteroaryl is a 5- or 6-membered aromatic ring which        contains 1, 2, 3, or 4 heteroatoms independently of each other        selected from N, O and S, wherein the H-atom in one or more NH        groups may be optionally replaced by R^(N); and    -   wherein heterocyclyl is a 4- to 7-membered unsaturated or        saturated carbocyclic ring in which 1 or 2-CH₂-groups        independently of each other are replaced by NR^(N), O, —C(═O)—,        S, —S(═O)— or —S(═O)₂—, and/or in which a —CH-group is replaced        by N; and    -   wherein each aryl, heteroaryl or heterocyclyl group may be        optionally substituted with one or more substituents        independently of each other selected from L^(A);        including any tautomers and stereoisomers thereof,        or a salt thereof        or a solvate or hydrate thereof,        with the proviso that the following compounds I-a, I-b, and I-c        are excluded:

In a further aspect the present invention relates to processes forpreparing a compound of general formula I and to new intermediatecompounds in these processes.

A further aspect of the invention relates to a salt of the compounds ofgeneral formula I according to this invention, in particular to apharmaceutically acceptable salt thereof, except for the salts of thecompounds I-a, I-b, and I-c.

In a further aspect this invention relates to a pharmaceuticalcomposition, comprising one or more compounds of general formula Iincluding the compounds I-a, I-b, and I-c or one or morepharmaceutically acceptable salts thereof according to the invention,optionally together with one or more inert carriers and/or diluents.

In a further aspect this invention relates to a method for treatingdiseases or conditions which are mediated by activating theG-protein-coupled receptor GPR119 in a patient in need thereofcharacterized in that a compound of general formula I including thecompounds I-a, I-b, and I-c or a pharmaceutically acceptable saltthereof is administered to the patient.

According to another aspect of the invention, there is provided a methodfor treating a metabolic disease or disorder in a patient in needthereof characterized in that a compound of general formula I includingthe compounds I-a, I-b, and I-c or a pharmaceutically acceptable saltthereof is administered to the patient.

According to another aspect of the invention, there is provided the useof a compound of the general formula I including the compounds I-a, I-b,and I-c or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for a therapeutic method as describedhereinbefore and hereinafter.

According to another aspect of the invention, there is provided acompound of the general formula I including the compounds I-a, I-b, andI-c or a pharmaceutically acceptable salt thereof for use in atherapeutic method as described hereinbefore and hereinafter.

In a further aspect this invention relates to a method for treating adisease or condition mediated by the activation of the G-protein-coupledreceptor GPR119 in a patient that includes the step of administering tothe patient in need of such treatment a therapeutically effective amountof a compound of the general formula I including the compounds I-a, I-b,and I-c or a pharmaceutically acceptable salt thereof in combinationwith a therapeutically effective amount of one or more additionaltherapeutic agents.

In a further aspect this invention relates to a use of a compound of thegeneral formula I including the compounds I-a, I-b, and I-c or apharmaceutically acceptable salt thereof in combination with one or moreadditional therapeutic agents for the treatment of diseases orconditions which are mediated by the activation of the G-protein-coupledreceptor GPR119.

In a further aspect this invention relates to a pharmaceuticalcomposition which comprises a compound according to general formula Iincluding the compounds I-a, I-b, and I-c or a pharmaceuticallyacceptable salt thereof and one or more additional therapeutic agents,optionally together with one or more inert carriers and/or diluents.

Other aspects of the invention become apparent to those skilled in theart from the specification and the experimental part as describedhereinbefore and hereinafter.

DETAILED DESCRIPTION

Unless otherwise stated, the groups, residues, and substituents,particularly A, R¹, R², T, R^(N), R^(NT1), R^(NT2), L^(A), and R^(C) aredefined as above and hereinafter. If residues, substituents, or groupsoccur several times in a compound, as for example R^(N) and L^(A), theymay have the same or different meanings. Some preferred meanings ofindividual groups and substituents of the compounds according to theinvention will be given hereinafter. Any and each of these definitionsmay be combined with each other.

R¹:

R¹-G1:

The group R¹ is preferably selected from the group R¹-G1 as definedhereinbefore and hereinafter.

R¹-G2:

According to one embodiment the group R¹ is selected from the groupR¹-G2 consisting of:

a) a group selected from:

wherein each group may be optionally substituted with one substituentL^(A) and one substituent R^(c);b) a group selected from —C(═O)—O—(C₁₋₄-alkyl)

and

-   -   wherein each alkyl residue may be optionally substituted with        one or more fluorine atoms; and        c) a group selected from:

R¹-G2a:

According to one embodiment the group R¹ is selected from the groupR¹-G2a consisting of

wherein each group may be optionally substituted with one substituentL^(A) and one substituent R^(C).R¹-G3:

In another embodiment the group R¹ is selected from the group R¹-G3consisting of:

a) a group selected from:

wherein each ring may be optionally substituted with one substituentR^(C);b) a group selected from:

wherein each alkyl residue may be optionally substituted with one ormore fluorine atoms; andc) a group selected from:

R¹-G3a:

In another embodiment the group R¹ is selected from the group R¹-G3aconsisting of

wherein each ring may be optionally substituted with one substituentR^(C). Preferably, R^(c) is selected from the group consisting of Cl,CF₃ and C₁₋₃-alkyl.R¹-G3b:

In another embodiment the group R¹ is selected from the group R¹-G3bconsisting of

R¹-G3c:

In another embodiment the group R¹ is selected from the group R¹-G3cconsisting of

R¹-G4:

In another embodiment the group R¹ is selected from the group R¹-G4consisting of

R²:R²-G1:

The group R² is preferably selected from the group R²-G1 as definedhereinbefore and hereinafter.

R²-G2:

According to another embodiment the group R² is selected from the groupR²-G2 consisting of H and CH₃.

R²-G3:

According to another embodiment the group R² is selected from the groupR²-G3 consisting of H.

R²-G4:

According to another embodiment the group R² is selected from the groupR²-G4 consisting of H₃C—.

A:

A-G1:

The group A is preferably selected from the group A-G1 as definedhereinbefore and hereinafter.

A-G2:

In one embodiment the group A is selected from the group A-G2 consistingof

-   -   a) phenyl, oxazolyl, pyridyl, pyrazinyl, pyridazinyl, and        pyrimidinyl, wherein each ring may be substituted with a group T        and is optionally substituted with one or two groups        independently of each other selected from L^(A); and    -   b) 1,2,3,6-tetrahydropyridin-4-yl and piperazin-1-yl, each of        which is substituted at the N with a C₁₋₃-alkyl-S(═O)₂— group.        A-G3:

In another embodiment the group A is selected from the group A-G3consisting of

-   -   which is substituted with a group T and may be additionally        substituted with one or two groups independently selected from F        and H₃C—; and

A-G4:

In another embodiment the group A is selected from the group A-G4consisting of

-   -   which may be additionally substituted with one or two F atoms,        and    -   wherein the group T is defined as hereinbefore and hereinafter;        and

A-G4a:

In another embodiment the group A is selected from the group A-G4aconsisting of

which may be additionally substituted with one F atom, andwherein the group T is defined as hereinbefore and hereinafter.A-G4b:

In another embodiment the group A is selected from the group A-G4bconsisting of

A-G5:

In another embodiment the group A is selected from the group A-G5consisting of:

A-G6:

In another embodiment the group A is selected from the group A-G6consisting of

TT-G1:

The group T is preferably selected from the group T-G1 as definedhereinbefore and hereinafter.

T-G2:

According to one embodiment the group T is selected from the group T-G2consisting of F, Cl, Br, CN, OH, NO₂, C₁₋₄-alkyl, C₁₋₄-alkyl-O—,C₁₋₄-alkyl-O—C(═O)—, C₁₋₄-alkyl-C(═O)—, C₁₋₄-alkyl-S(═O)—,C₁₋₄-alkyl-S(═O)₂—, C₁₋₄-alkyl-S(═O)₂—C₁₋₄-alkyl-,R^(NT1)R^(NT2)N—C(═O)—, R^(NT1)R^(NT2)N—S(═O)₂—,C₁₋₄-alkyl-S(═O)₂—(R^(N))N—, R^(NT1)R^(NT2)N—,R^(NT1)R^(NT2)N—C(═O)—C₁₋₄-alkyl-,

-   -   wherein each alkyl-group may be optionally substituted with one        or more substituents independently of each other selected from        F, Cl, CN, OH, aryl, heteroaryl, and heterocyclyl,    -   wherein aryl denotes phenyl or naphthyl,    -   wherein heteroaryl is selected from the group consisting of        pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl,        imidazolyl, [1,2,4]triazolyl and tetrazolyl;    -   wherein heterocyclyl is selected from the group consisting of        azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and        morpholinyl, in each of which a group may be optionally replaced        by a group selected from —C(═O)— and —S(═O)₂—, wherein        heterocyclyl group may be optionally substituted with one or        more substituents independently of each other selected from        C₁₋₃-alkyl; and    -   wherein each phenyl and heteroaryl may be optionally substituted        with one or more substituents L^(A), wherein the substituents        may be identical or different.        T-G3:

According to another embodiment the group T is selected from the groupT-G3 consisting of —CN, C₁₋₄-alkyl-S(═O)₂—CH₂—, C₁₋₄-alkyl-S(═O)₂—,R^(NT1)R^(NT2)N—S(═O)₂—, R^(NT1)R^(NT2)N—C(═O)—,C₁₋₄-alkyl-S(═O)₂—(R^(N))N—, and R^(NT1)R^(NT2)N—.

T-G4:

According to another embodiment the group T is selected from the groupT-G4 consisting of NC—, C₁₋₄-alkyl-S(═O)₂—CH₂—, C₁₋₄-alkyl-S(═O)₂,(C₁₋₄-alkyl)NH—C(═O)—, and C₁₋₄-alkyl-S(═O)₂—NH—.

T-G5:

According to another embodiment the group T is selected from the groupT-G5 consisting of NC—, H₂N—C(═O)—, CH₃—CH₂—NH—C(═O)—, CH₃—S(═O)₂—CH₂—,and CH₃—S(═O)₂—.

R^(N)

R^(N)-G1:

The group R^(N) is preferably selected from the group R^(N)-G1 asdefined hereinbefore and hereinafter.

R^(N)-G2:

In another embodiment the group R^(N) is selected from the groupR^(N)-G2 consisting of H, methyl, ethyl, isopropyl, methylcarbonyl, andmethylsulfonyl.

R^(N)-G3:

In another embodiment the group R^(N) is selected from the groupR^(N)-G3 consisting of H, methyl, methylcarbonyl, and methylsulfonyl.

R^(N)-G4:

In another embodiment the group R^(N) is selected from the groupR^(N)-G4 consisting of H and methyl.

R^(NT1)

R^(NT1)-G1:

R^(NT1) is preferably selected from the group R^(NT1)-G1 as definedhereinbefore and hereinafter.

R^(NT1)-G2:

In another embodiment R^(NT1) is selected from the group R^(NT1)-G2consisting of H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl and tetrahydropyranyl,

-   -   wherein each alkyl and cycloalkyl group may be optionally        substituted with one substituent selected from the group        consisting of F, CH₃, OH, C₁₋₃-alkyl-O—, (R^(N))₂N—, CN,        tetrahydrofuranyl, 1,4-dioxinyl, oxazolyl, and pyridyl.        R^(NT1)-G3:

In another embodiment R^(NT1) is selected from the group R^(NT1)-G3consisting of H, C₁₋₄-alkyl and C₃₋₆-cycloalkyl,

-   -   wherein each alkyl and cycloalkyl group may be optionally        substituted with one substituent selected from F, CH₃, OH, and        C₁₋₃-alkyl-O—.        R^(NT2)-G4:

In another embodiment R^(NT1) is selected from the group R^(NT1)-G4consisting of H and C₁₋₄-alkyl.

R^(NT2)

R^(NT2)-G1:

R^(NT2) is preferably selected from the group R^(NT2)-G1 as definedhereinbefore and hereinafter.

R^(NT2)-G2:

In another embodiment R^(NT2) is selected from the group R^(NT2)-G2consisting of H and C₁₋₃-alkyl.

R^(NT2)-G3:

In another embodiment R^(NT2) is selected from the group R^(NT2)-G3consisting of H and methyl.

R^(NT2)-G4:

In another embodiment R^(NT2) is selected from the group R^(NT2)-G4consisting of H.

R^(NT1)R^(NT2)

R^(NT1)R^(NT2)-G1:

According to one embodiment the groups R^(NT1) and R^(NT2) are linkedand form a group which is selected from the group R^(NT1)R^(NT2)-G1 asdefined hereinbefore and hereinafter.

R^(NT1)R^(NT2)-G2:

According to another embodiment the groups R^(NT1) and R^(NT2) arelinked and together with the N-atom to which they are attached form agroup which is selected from the group R^(NT1)R^(NT2)-G2 consisting of:

azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,piperazin-2-onyl, N—(C₁₋₃-alkyl)-piperazinyl,N—(C₁₋₃-alkyl)-piperazin-2-onyl, and N—(C₁₋₃-alkyl-C(═O))-piperazinyl,

-   -   which may be optionally substituted with one or more        substituents independently of each other selected from the group        consisting of F, HO, C₁₋₃-alkyl, C₁₋₃-alkyl-O—, and (R^(N))₂N—.        R^(NT1)R^(NT2)-G3:

According to another embodiment the groups R^(NT1) and R^(NT2) arelinked and together with the N-atom to which they are attached form agroup which is selected from the group R^(NT1)R^(NT2)-G3 consisting of:

azetidinyl, pyrrolidinyl, piperidinyl, and morpholinyl, each of whichmay be optionally substituted with one or two substituents independentlyof each other selected from the group consisting of F, OH, CH₃ andCH₃—O—.

L^(A):

L^(A)-G1:

The group L^(A) is preferably selected from the group L^(A)-G1 asdefined hereinbefore and hereinafter.

L^(A)-G2:

In another embodiment the group L^(A) is selected from the groupL^(A)-G2 consisting of F, Cl, Br, CN, OH, C₁₋₃-alkyl-, C₁₋₃-alkyl-O—,H₂N—, C₁₋₃-alkyl-NH— and (C₁₋₃-alkyl)₂N—, wherein the C₁₋₃-alkyl- andC₁₋₃-alkyl-O— group may be optionally substituted with one or moreF-atoms.

L^(A)-G3:

In another embodiment the group L^(A) is selected from the groupL^(A)-G3 consisting of F, Cl, CH₃, and CF₃.

L^(A)-G4:

In another embodiment the group L^(A) is selected from the groupL^(A)-G4 consisting of F.

R^(C):

R^(C)-G1:

The group R^(C) is preferably selected from the group R^(C)-G1 asdefined hereinbefore and hereinafter.

R^(C)-G2:

According to one embodiment the group R^(C) is selected from the groupR^(C)-G2 consisting of F, Cl, Br, I, CN, OH, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₃₋₆-cycloalkyl, C₁₋₆-alkyl-O—, C₃₋₆-cycloalkyl-O—,C₁₋₆-alkyl-S—, C₁₋₆-alkyl-O—C(═O)—, C₁₋₄-alkyl-S(═O)—,C₁₋₄-alkyl-S(═O)—C₁₋₄-alkyl-, C₁₋₄-alkyl-S(═O)₂—,C₁₋₄-alkyl-S(═O)₂—C₁₋₄-alkyl-, R^(NT1)R^(NT2)N—,R^(NT1)R^(NT2)N—C₁₋₃-alkyl-, R^(NT1)R^(NT2)N—C(═O)—,R^(NT1)R^(NT2)N—S(═O)₂—, R^(NT1)R^(NT2)N—S(═O)₂—C₁₋₄-alkyl-,R^(NT1)R^(NT2)N—C(═O)—C₁₋₄-alkyl-, heterocyclyl, heterocyclyl-O—, andphenyl,

-   -   wherein each alkyl, alkenyl, alkynyl, and cycloalkyl group may        be optionally substituted with one or more fluorine atoms and a        substituent selected from Cl, CN, OH, C₁₋₃-alkyl,        C₃₋₆-cycloalkyl, C₁₋₃-alkyl-O—, and heterocyclyl;    -   wherein heterocyclyl is selected from the group consisting of        pyrrolidin-2-onyl, piperidin-2-onyl, piperazin-2-onyl,        morpholinyl, morpholin-3-onyl, oxetanyl, tetrahydrofuranyl, and        tetrahydropyranyl, each of which may be optionally substituted        with one or two H₃C— groups; and    -   wherein phenyl may be optionally substituted independently of        each other with one or more substituents L^(A).        R^(C)-G3:

According to another embodiment the group R^(C) is selected from thegroup R^(C)-G3 consisting of F, Cl, Br, CN, C₁₋₄-alkyl, C₃₋₆-cycloalkyl,C₁₋₄-alkyl-O—, C₃₋₆-cycloalkyl-O—, heterocyclyl, and heterocyclyl-O—,

-   -   wherein each alkyl and cycloalkyl group may be optionally        substituted with one or more fluorine atoms and a substituent        selected from H₃C— and H₃C—O—, and    -   wherein heterocyclyl is selected from the group consisting of        oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl, each of        which may be optionally substituted with one or two H₃C— groups.        R^(C)-G4:

According to another embodiment the group R^(C) is selected from thegroup R^(C)-G4 consisting of Cl, C₁₋₄-alkyl, F₃C—, C₃₋₄-cycloalkyl, andC₁₋₃-alkyl-O—.

R^(C)-G5:

According to another embodiment the group R^(C) is selected from thegroup R^(C)-G5 consisting of Cl, F₃C— and C₁₋₃-alkyl.

A preferred embodiment of compounds of the formula I are described byformula (I.1), wherein any tautomers and stereoisomers, solvates,hydrates and salts thereof, in particular the pharmaceuticallyacceptable salts thereof, are encompassed.

Examples of preferred subgeneric embodiments according to the presentinvention are set forth in the following table, wherein each substituentgroup of each embodiment is defined according to the definitions setforth hereinbefore and wherein all other substituents of the formula Iare defined according to the definitions as set forth hereinbefore:

Embodiment R¹- A- T- R^(C)- E-1 R¹-G1 A-G1 T-G1 R^(C)-G1 E-2 R¹-G2 A-G2T-G3 R^(C)-G3 E-3 R¹-G2 A-G2 T-G3 R^(C)-G4 E-4 R¹-G2 A-G2 T-G3 R^(C)-G5E-5 R¹-G2 A-G2 T-G4 R^(C)-G3 E-6 R¹-G2 A-G2 T-G4 R^(C)-G4 E-7 R¹-G2 A-G2T-G4 R^(C)-G5 E-8 R¹-G2 A-G2 T-G5 R^(C)-G3 E-9 R¹-G2 A-G2 T-G5 R^(C)-G4E-10 R¹-G2 A-G2 T-G5 R^(C)-G5 E-11 R¹-G2 A-G3 T-G3 R^(C)-G3 E-12 R¹-G2A-G3 T-G3 R^(C)-G4 E-13 R¹-G2 A-G3 T-G3 R^(C)-G5 E-14 R¹-G2 A-G3 T-G4R^(C)-G3 E-15 R¹-G2 A-G3 T-G4 R^(C)-G4 E-16 R¹-G2 A-G3 T-G4 R^(C)-G5E-17 R¹-G2 A-G3 T-G5 R^(C)-G3 E-18 R¹-G2 A-G3 T-G5 R^(C)-G4 E-19 R¹-G2A-G3 T-G5 R^(C)-G5 E-20 R¹-G2 A-G4 T-G3 R^(C)-G3 E-21 R¹-G2 A-G4 T-G3R^(C)-G4 E-22 R¹-G2 A-G4 T-G3 R^(C)-G5 E-23 R¹-G2 A-G4 T-G4 R^(C)-G3E-24 R¹-G2 A-G4 T-G4 R^(C)-G4 E-25 R¹-G2 A-G4 T-G4 R^(C)-G5 E-26 R¹-G2A-G4 T-G5 R^(C)-G3 E-27 R¹-G2 A-G4 T-G5 R^(C)-G4 E-28 R¹-G2 A-G4 T-G5R^(C)-G5 E-29 R¹-G2 A-G4a T-G3 R^(C)-G3 E-30 R¹-G2 A-G4a T-G3 R^(C)-G4E-31 R¹-G2 A-G4a T-G3 R^(C)-G5 E-32 R¹-G2 A-G4a T-G4 R^(C)-G3 E-33 R¹-G2A-G4a T-G4 R^(C)-G4 E-34 R¹-G2 A-G4a T-G4 R^(C)-G5 E-35 R¹-G2 A-G4a T-G5R^(C)-G3 E-36 R¹-G2 A-G4a T-G5 R^(C)-G4 E-37 R¹-G2 A-G4a T-G5 R^(C)-G5E-38 R¹-G2 A-G4b — R^(C)-G3 E-39 R¹-G2 A-G4b — R^(C)-G4 E-40 R¹-G2 A-G4b— R^(C)-G5 E-41 R¹-G2 A-G5 — R^(C)-G3 E-42 R¹-G2 A-G5 — R^(C)-G4 E-43R¹-G2 A-G5 — R^(C)-G5 E-44 R¹-G3 A-G2 T-G3 R^(C)-G3 E-45 R¹-G3 A-G2 T-G3R^(C)-G4 E-46 R¹-G3 A-G2 T-G3 R^(C)-G5 E-47 R¹-G3 A-G2 T-G4 R^(C)-G3E-48 R¹-G3 A-G2 T-G4 R^(C)-G4 E-49 R¹-G3 A-G2 T-G4 R^(C)-G5 E-50 R¹-G3A-G2 T-G5 R^(C)-G3 E-51 R¹-G3 A-G2 T-G5 R^(C)-G4 E-52 R¹-G3 A-G2 T-G5R^(C)-G5 E-53 R¹-G3 A-G3 T-G3 R^(C)-G3 E-54 R¹-G3 A-G3 T-G3 R^(C)-G4E-55 R¹-G3 A-G3 T-G3 R^(C)-G5 E-56 R¹-G3 A-G3 T-G4 R^(C)-G3 E-57 R¹-G3A-G3 T-G4 R^(C)-G4 E-58 R¹-G3 A-G3 T-G4 R^(C)-G5 E-59 R¹-G3 A-G3 T-G5R^(C)-G3 E-60 R¹-G3 A-G3 T-G5 R^(C)-G4 E-61 R¹-G3 A-G3 T-G5 R^(C)-G5E-62 R¹-G3 A-G4 T-G3 R^(C)-G3 E-63 R¹-G3 A-G4 T-G3 R^(C)-G4 E-64 R¹-G3A-G4 T-G3 R^(C)-G5 E-65 R¹-G3 A-G4 T-G4 R^(C)-G3 E-66 R¹-G3 A-G4 T-G4R^(C)-G4 E-67 R¹-G3 A-G4 T-G4 R^(C)-G5 E-68 R¹-G3 A-G4 T-G5 R^(C)-G3E-69 R¹-G3 A-G4 T-G5 R^(C)-G4 E-70 R¹-G3 A-G4 T-G5 R^(C)-G5 E-71 R¹-G3A-G4a T-G3 R^(C)-G3 E-72 R¹-G3 A-G4a T-G3 R^(C)-G4 E-73 R¹-G3 A-G4a T-G3R^(C)-G5 E-74 R¹-G3 A-G4a T-G4 R^(C)-G3 E-75 R¹-G3 A-G4a T-G4 R^(C)-G4E-76 R¹-G3 A-G4a T-G4 R^(C)-G5 E-77 R¹-G3 A-G4a T-G5 R^(C)-G3 E-78 R¹-G3A-G4a T-G5 R^(C)-G4 E-79 R¹-G3 A-G4a T-G5 R^(C)-G5 E-80 R¹-G3 A-G4b —R^(C)-G3 E-81 R¹-G3 A-G4b — R^(C)-G4 E-82 R¹-G3 A-G4b — R^(C)-G5 E-83R¹-G3 A-G5 — R^(C)-G3 E-84 R¹-G3 A-G5 — R^(C)-G4 E-85 R¹-G3 A-G5 —R^(C)-G5 E-86 R¹-G4 A-G2 T-G3 — E-87 R¹-G4 A-G2 T-G4 — E-88 R¹-G4 A-G2T-G5 — E-89 R¹-G4 A-G3 T-G3 — E-90 R¹-G4 A-G3 T-G4 — E-91 R¹-G4 A-G3T-G5 — E-92 R¹-G4 A-G4 T-G3 — E-93 R¹-G4 A-G4 T-G4 — E-94 R¹-G4 A-G4T-G5 — E-95 R¹-G4 A-G4a T-G3 — E-96 R¹-G4 A-G4a T-G4 — E-97 R¹-G4 A-G4aT-G5 — E-98 R¹-G4 A-G4b — — E-99 R¹-G4 A-G5 — — E-100 R¹-G3a A-G4 T-G3R^(C)-G3 E-101 R¹-G3a A-G4 T-G3 R^(C)-G4 E-102 R¹-G3a A-G4 T-G3 R^(C)-G5E-103 R¹-G3a A-G4 T-G4 R^(C)-G3 E-104 R¹-G3a A-G4 T-G4 R^(C)-G4 E-105R¹-G3a A-G4 T-G4 R^(C)-G5 E-106 R¹-G3a A-G4 T-G5 R^(C)-G3 E-107 R¹-G3aA-G4 T-G5 R^(C)-G4 E-108 R¹-G3a A-G4 T-G5 R^(C)-G5 E-109 R¹-G3a A-G4aT-G3 R^(C)-G3 E-110 R¹-G3a A-G4a T-G3 R^(C)-G4 E-111 R¹-G3a A-G4a T-G3R^(C)-G5 E-112 R¹-G3a A-G4a T-G4 R^(C)-G3 E-113 R¹-G3a A-G4a T-G4R^(C)-G4 E-114 R¹-G3a A-G4a T-G4 R^(C)-G5 E-115 R¹-G3a A-G4a T-G5R^(C)-G3 E-116 R¹-G3a A-G4a T-G5 R^(C)-G4 E-117 R¹-G3a A-G4a T-G5R^(C)-G5 E-118 R¹-G3a A-G4b — R^(C)-G3 E-119 R¹-G3a A-G4b — R^(C)-G4E-120 R¹-G3a A-G4b — R^(C)-G5 E-121 R¹-G3b A-G4 T-G3 — E-122 R¹-G3b A-G4T-G4 — E-123 R¹-G3b A-G4 T-G5 — E-124 R¹-G3b A-G4a T-G3 — E-125 R¹-G3bA-G4a T-G4 — E-126 R¹-G3b A-G4a T-G5 — E-127 R¹-G3b A-G4b — — E-128R¹-G2 A-G6 — R^(C)-G3 E-129 R¹-G2 A-G6 — R^(C)-G4 E-130 R¹-G2 A-G6 —R^(C)-G5 E-131 R¹-G3 A-G6 — R^(C)-G3 E-132 R¹-G3 A-G6 — R^(C)-G4 E-133R¹-G3 A-G6 — R^(C)-G5 E-134 R¹-G4 A-G6 — —

Preferred are those compounds of formula I, wherein

R¹ is selected from the group consisting of:

-   -   wherein each ring may be optionally substituted with one        substituent R^(C); and wherein R^(C) is selected from the group        consisting of Cl, C₁₋₄-alkyl, F₃C—, C₃₋₄-cycloalkyl, and        C₁₋₃-alkyl-O—;

-   -   wherein each alkyl residue may be optionally substituted with        one or more fluorine atoms; and

R² is H; and

A is selected from the group consisting of:

-   -   wherein T is selected from the group consisting of NC—,        C₁₋₄-alkyl-S(═O)₂—CH₂—, C₁₋₄-alkyl-S(═O)₂,        R^(NT1)R^(NT2)N—C(═O)—, and C₁₋₄-alkyl-S(═O)₂—NH—; and which may        be additionally substituted with one or two F atoms; and

and the pharmaceutically acceptable salts thereof.

More preferred are those compounds of formula I, wherein

R¹ is selected from the group consisting of:

-   -   wherein each ring may be optionally substituted with one        substituent R^(C); and    -   wherein R^(C) is selected from the group consisting of Cl,        C₁₋₄-alkyl, F₃C—, C₃₋₄-cycloalkyl, and C₁₋₃-alkyl-O—;

-   -   wherein each alkyl residue may be optionally substituted with        one or more fluorine atoms; and

and

R² is H; and

A is selected from the group consisting of:

and the pharmaceutically acceptable salts thereof.

Particularly preferred compounds, including their tautomers andstereoisomers, the salts thereof, or any solvates or hydrates thereof,are described in the experimental section hereinafter.

The compounds according to the invention and their intermediates may beobtained using methods of synthesis which are known to those skilled inthe art and described in the literature of organic synthesis. Preferablythe compounds are obtained analogously to the methods of preparationexplained more fully hereinafter, in particular as described in theexperimental section. In some cases the sequence adopted in carrying outthe reaction schemes may be varied. Variants of these reactions that areknown to a person skilled in the art but are not described in detailhere may also be used. The general processes for preparing the compoundsaccording to the invention will become apparent to a person skilled inthe art on studying the schemes that follow. Starting compounds arecommercially available or may be prepared by methods that are describedin the literature or herein, or may be prepared in an analogous orsimilar manner. Before the reaction is carried out any correspondingfunctional groups in the compounds may be protected using conventionalprotecting groups. These protecting groups may be cleaved again at asuitable stage within the reaction sequence using methods familiar to aperson skilled in the art.

Compounds of the invention I may be obtained from compound 1, bearingtwo replaceable halogen or pseudo-halogen groups, as described in Scheme1; R¹, R², and A have the meanings as defined hereinbefore andhereinafter. Depending on the reactivity of the two carbon atoms bearingthe halogen or pseudo-halogen groups, the two coupling partners, 3 and5, are introduced following the sequence depicted on the top or bottomof the scheme. Both residues are preferably attached via a transitionmetal catalyzed reaction, preferably mediated by a palladium, nickel,copper, or iron species. The active catalyst may be derived from anelemental form of the transition metal, such as palladium on carbon ornanoparticles of iron or palladium, or a salt of the transition metal,such as fluoride, chloride, bromide, acetate, triflate, ortrifluoroacetate, which are preferably combined with ligands, such asphosphines, e.g. tri-tert-butylphosphine, tricyclohexylphosphine,optionally substituted biphenyl-dicyclohexyl-phosphines, optionallysubstituted biphenyl-di-tert-butyl-phosphines,1,1′-bis(diphenylphosphino)-ferrocene, triphenylphosphine,tritolylphosphine, or trifurylphosphine, phosphites, 1,3-disubstitutedimidazole carbenes, 1,3-disubstituted imidazolidine carbenes,dibenzylideneacetone, allyl, or nitriles. A-M is preferably a boronicacid, trifluoroborate, boronic ester, zinc halide, or magnesium halideof A and alkyne 3 is preferably used as is or zinc acetylide. Dependingon the nucleophiles the reactions are preferably conducted in benzene,toluene, ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone,alcohol, water, or mixtures thereof, at −10 to 180° C. Additives such ashalide salts, e.g. lithium chloride, potassium fluoride,tetrabutylammonium fluoride, hydroxide sources, such as potassiumhydroxide, potassium carbonate, amines, such as triethylamine,diisopropylamine, and ethyldiisopropylamine, silver salts, such assilver oxide or triflate, and/or copper salts, such as copper iodide orchloride or copper thiophene-2-carboxylate, may be beneficial or evenessential for the reaction to proceed. The conditions for the couplingof alkyne 3 with one of the electrophiles, 1 or 4, may bring about thesubsequent cyclization as well and thus provide the benzofuran. Forinstance, with Pd(PPh₃)₂Cl₂, CuI, and triethylamine inN,N-dimethylformamide at 20 to 140° C. the benzofuran may be obtaineddirectly. If the intermediate alkyne 6 is obtained the benzofuran may beformed in a separate step using, for example, n-Bu₄NF in tetrahydrofuranat 50 to 70° C., NaOH in aqueous solution at elevated temperature, CuIor CuCN, optionally in the presence of NEt₃, in N,N-dimethylformamide atelevated temperature, AuCl(PPh₃) and AgOSO₂CF₃ in CH₂Cl₂ ortetrahydrofuran, AgOSO₂CF₃, optionally in the presence oftrifluoroacetic acid, in CH₂Cl₂, Pd, e.g. PdCl₂, or other transitionmetals such as Rh. The reactivities of the reaction partners (reactingcarbons) described may be reversed, i.e. compounds 1, 2, and 4 are thenucleophile bearing M and compounds 3 and 5 are the electrophile bearingHal¹ or Hal², providing the same products under the same or similarconditions.

Residue R¹ is attached to the N atom of the piperidine of the compoundsof the invention via different routes depending on the nature of residueR¹ (Scheme 2); R¹, R², and A have the meanings as defined hereinbeforeand hereinafter. A heteroaryl group may be attached via a nucleophilicsubstitution of a leaving group on the heteroaromatic, such as F, Cl,Br, SO₂C₁₋₄-alkyl, and SO₂aryl. The reaction is preferably conducted inthe presence of a base, e.g. Na₂CO₃, K₂CO₃, CS₂CO₃, triethylamine,ethyldiisopropylamine, and 1,8-diazabicylo[5.4.0]undec-7-ene, intoluene, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,N-methylpyrrolidinone, water, alcohol, dimethyl sulfoxide, or mixturesthereof, at 20 to 220° C. by conventional or microwave heating. Incertain cases the use of transition metal catalysts may be beneficial oreven essential. The leaving group Y in compound 8 is then preferably Cl,Br, I, and OSO₂CF₃. Some heteroaromatic residues R¹ such as[1,2,4]oxadiazoles may also be assembled from the correspondingcyanamide of compound 7 and N-hydroxyamidine.

A carbamate group may be formed from compound 7 and an oxycarbonylelectrophile (R¹═R^(a)O—C(═O)), such as R^(a)O—C(═O)—Cl orR^(a)O—C(═O)—O—C(═O)—OR^(a)). The reaction is usually conducted in thepresence of a base, e.g. K₂CO₃, pyridine, 4-dimethylaminopyridine,triethylamine, or ethyldiisopropylamine, in a solvent such as toluene,dichloromethane, ether, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane, acetonitrile, or mixtures thereof, at −10 to 120°C.

A methylene group may be attached to the piperidine N by using an R¹group bearing a leaving group at the CH₂ unit to be attached, such asCl, Br, I, OSO₂C₁₋₄-alkyl, OSO₂aryl, or OSO₂CF₃. The substitution iscommonly done in the presence of a base, e.g. Na₂CO₃, K₂CO₃, Cs₂CO₃,pyridine, triethylamine, ethyldiisopropylamine, and1,8-diazabicylo[5.4.0]undec-7-ene, in a solvent such as toluene,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, acetonitrile,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone,water, methanol, ethanol, isopropanol, dimethyl sulfoxide, or mixturesthereof, at 20 to 220° C. by conventional or microwave heating.

Alternatively, the CH₂ moiety of residue R¹ is formed during theattachment reaction by reductive alkylation employing R¹ as aldehyde anda reducing agent, such as NaH₃BCN or NaHB(O₂CCH₃)₃. Using a carboxylicacid derivative of R¹ also allows the attachment of R¹ to intermediate 7via a CH₂ unit by a two step procedure, amide coupling followed byreduction of the amide carbonyl group.

The proceedings described for attaching group R¹ to the N of thepiperidine moiety may be employed for any suited precursor molecule ofcompound 7, too, such as compound 3 in Scheme 1.

The synthetic routes presented may rely on the use of protecting groups.For example, potentially reactive groups present, such as hydroxy,carbonyl, carboxy, amino, alkylamino, or imino, may be protected duringthe reaction by conventional protecting groups which are cleaved againafter the reaction. Suitable protecting groups for the respectivefunctionalities and their removal are well known to a person skilled inthe art and are described in the literature of organic synthesis.

The compounds of general formula I may be resolved into theirenantiomers and/or diastereomers as mentioned before. Thus, for example,cis/trans mixtures may be resolved into their cis and trans isomers andracemic compounds may be separated into their enantiomers.

The cis/trans mixtures may be resolved, for example, by chromatographyinto the cis and trans isomers thereof. The compounds of general formulaI which occur as racemates may be separated by methods known per se intotheir optical antipodes and diastereomeric mixtures of compounds ofgeneral formula I may be resolved into their diastereomers by takingadvantage of their different physico-chemical properties using methodsknown per se, e.g. chromatography and/or fractional crystallization; ifthe compounds obtained thereafter are racemates, they may be resolvedinto the enantiomers as mentioned above.

The racemates are preferably resolved by column chromatography on chiralphases or by crystallization from an optically active solvent or byreacting with an optically active substance which forms salts orderivatives such as esters or amides with the racemic compound. Saltsmay be formed with enantiomerically pure acids for basic compounds andwith enantiomerically pure bases for acidic compounds. Diastereomericderivatives are formed with enantiomerically pure auxiliary compounds,e.g. acids, their activated derivatives, or alcohols. Separation of thediastereomeric mixture of salts or derivatives thus obtained may beachieved by taking advantage of their different physico-chemicalproperties, e.g. differences in solubility; the free antipodes may bereleased from the pure diastereomeric salts or derivatives by the actionof suitable agents. Optically active acids commonly used for such apurpose as well as optically active alcohols applicable as auxiliaryresidues are known to those skilled in the art.

As mentioned above, the compounds of formula I may be converted intosalts, particularly for pharmaceutical use into the pharmaceuticallyacceptable salts. As used herein, “pharmaceutically acceptable salts”refer to derivatives of the disclosed compounds wherein the parentcompound is modified by making acid or base salts thereof.

The compounds according to the invention are advantageously alsoobtainable using the methods described in the examples that follow,which may also be combined for this purpose with methods known to aperson skilled in the art from the literature.

TERMS AND DEFINITIONS

Terms not specifically defined herein have the meaning that a personskilled in the art would attribute to in light of the disclosure and thecontext. As used in the specification, however, unless specified to thecontrary, the following terms have the meaning indicated and thefollowing conventions are adhered to.

The terms “compound(s) according to this invention”, “compound(s) offormula (I)”, “compound(s) of the invention” and the like denote thecompounds of the formula (I) according to the present inventionincluding their tautomers, stereoisomers and mixtures thereof and thesalts thereof, in particular the pharmaceutically acceptable saltsthereof, and the solvates and hydrates of such compounds, including thesolvates and hydrates of such tautomers, stereoisomers and saltsthereof.

The terms “treatment” and “treating” embrace both preventative, i.e.prophylactic, or therapeutic, i.e. curative and/or palliative,treatment. Thus the terms “treatment” and “treating” comprisetherapeutic treatment of patients having already developed saidcondition, in particular in manifest form. Therapeutic treatment may besymptomatic treatment in order to relieve the symptoms of the specificindication or causal treatment in order to reverse or partially reversethe conditions of the indication or to stop or slow down progression ofthe disease. Thus the compositions and methods of the present inventionmay be used for instance as therapeutic treatment over a period of timeas well as for chronic therapy. In addition the terms “treatment” and“treating” comprise prophylactic treatment, i.e. a treatment of patientsat risk to develop a condition mentioned hereinbefore, thus reducingsaid risk.

When this invention refers to patients requiring treatment, it relatesprimarily to treatment in mammals, in particular humans.

The term “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease or condition, (ii) attenuates, ameliorates, oreliminates one or more symptoms of the particular disease or condition,or (iii) prevents or delays the onset of one or more symptoms of theparticular disease or condition described herein.

The terms “modulated” or “modulating”, or “modulate(s)”, as used herein,unless otherwise indicated, refer to the activation of theG-protein-coupled receptor GPR119 with one or more compounds of thepresent invention.

The terms “mediated” or “mediating” or “mediate”, as used herein, unlessotherwise indicated, refer to the (i) treatment, including prevention ofthe particular disease or condition, (ii) attenuation, amelioration, orelimination of one or more symptoms of the particular disease orcondition, or (iii) prevention or delay of the onset of one or moresymptoms of the particular disease or condition described herein.

The term “substituted” as used herein, means that any one or morehydrogens on the designated atom, radical or moiety is replaced with aselection from the indicated group, provided that the atom's normalvalence is not exceeded, and that the substitution results in anacceptably stable compound.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, C₁₋₆-alkylmeans an alkyl group or radical having 1 to 6 carbon atoms. In general,for groups comprising two or more subgroups, the last named subgroup isthe radical attachment point, for example, the substituent“aryl-C₁₋₃-alkyl-” means an aryl group which is bound to aC₁₋₃-alkyl-group, the latter of which is bound to the core or to thegroup to which the substituent is attached.

In case a compound of the present invention is depicted in form of achemical name and as a formula, the formula shall prevail in case of anydiscrepancy.

An asterisk is may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

The numeration of the atoms of a substituent starts with the atom whichis closest to the core or to the group to which the substituent isattached.

For example, the term “3-carboxypropyl-group” represents the followingsubstituent:

wherein the carboxy group is attached to the third carbon atom of thepropyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or“cyclopropylmethyl-” group represent the following groups:

The asterisk may be used in sub-formulas to indicate the bond which isconnected to the core molecule as defined.

In a definition of a group the term “wherein each X, Y and Z group isoptionally substituted with” and the like denotes that each group X,each group Y and each group Z either each as a separate group or each aspart of a composed group may be substituted as defined. For example adefinition “R^(ex) denotes H, C₁₋₃-alkyl, C₃₋₆-cycloalkyl,C₃₋₆-cycloalkyl-C₁₋₃-alkyl or C₁₋₃-alkyl-O—, wherein each alkyl group isoptionally substituted with one or more L^(ex).” or the like means thatin each of the beforementioned groups which comprise the term alkyl,i.e. in each of the groups C₁₋₃-alkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkyl andC₁₋₃-alkyl-O—, the alkyl moiety may be substituted with L^(ex) asdefined.

In the following the term bicyclic includes spirocyclic.

Unless specifically indicated, throughout the specification and theappended claims, a given chemical formula or name shall encompasstautomers and all stereo, optical and geometrical isomers (e.g.enantiomers, diastereomers, E/Z isomers etc. . . . ) and racematesthereof as well as mixtures in different proportions of the separateenantiomers, mixtures of diastereomers, or mixtures of any of theforegoing forms where such isomers and enantiomers exist, as well assalts, including pharmaceutically acceptable salts thereof and solvatesthereof such as for instance hydrates including solvates of the freecompounds or solvates of a salt of the compound.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication, andcommensurate with a reasonable benefit/risk ratio.

As used herein, the term “pharmaceutically acceptable salts” refers toderivatives of the disclosed compounds wherein the parent compound ismodified by making a salt thereof with a suitable organic or inorganicacid or base.

Salts that are for example useful for purifying or isolating thecompounds of the present invention are also an embodiment of theinvention.

The term halogen generally denotes fluorine, chlorine, bromine andiodine.

The term “C_(1-n)-alkyl”, wherein n is an integer from 1 to n, eitheralone or in combination with another radical denotes an acyclic,saturated, branched or linear hydrocarbon radical with 1 to n C atoms.For example the term C₁₋₅-alkyl embraces the radicals H₃C—, H₃C—CH₂—,H₃C—CH₂—CH₂—, H₃C—CH(CH₃)—, H₃C—CH₂—CH₂—CH₂—, H₃C—CH₂—CH(CH₃)—,H₃C—CH(CH₃)—CH₂—, H₃C—C(CH₃)₂—, H₃C—CH₂—CH₂—CH₂—CH₂—,H₃C—CH₂—CH₂—CH(CH₃)—, H₃C—CH₂—CH(CH₃)—CH₂—, H₃C—CH(CH₃)—CH₂—CH₂—,H₃C—CH₂—C(CH₃)₂—, H₃C—C(CH₃)₂—CH₂—, H₃C—CH(CH₃)—CH(CH₃)— andH₃C—CH₂—CH(CH₂CH₃)—.

The term “C_(1-n)-alkylene” wherein n is an integer 1 to n, either aloneor in combination with another radical, denotes an acyclic, straight orbranched chain divalent alkyl radical containing from 1 to n carbonatoms. For example the term C₁₋₄-alkylene includes —(CH₂)—, —(CH₂—CH₂)—,—(CH(CH₃))—, —(CH₂—CH₂—CH₂)—, —(C(CH₃)₂)—, —(CH(CH₂CH₃))—,—(CH(CH₃)—CH₂)—, —(CH₂—CH(CH₃))—, —(CH₂—CH₂—CH₂—CH₂)—,—(CH₂—CH₂—CH(CH₃))—, —(CH(CH₃)—CH₂—CH₂)—, —(CH₂—CH(CH₃)—CH₂)—,—(CH₂—C(CH₃)₂)—, —(C (CH₃)₂—CH₂)—, —(CH(CH₃)—CH(CH₃))—,—(CH₂—CH(CH₂CH₃))—, —(CH(CH₂CH₃)—CH₂)—, —(CH(CH₂CH₂CH₃))—,—(CHCH(CH₃)₂)— and —C(CH₃)(CH₂CH₃)—.

The term “C_(2-n)-alkenyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenyl includes —CH═CH₂,—CH═CH—CH₃, —CH₂—CH═CH₂.

The term “C_(2-n)-alkenylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a double bond. For example the term C₂₋₃-alkenylene includes —CH═CH—,—CH═CH—CH₂—, —CH₂—CH═CH—.

The term “C_(2-n)-alkynyl”, is used for a group as defined in thedefinition for “C_(1-n)-alkyl” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynyl includes —C≡CH,—C≡C—CH₃, —CH₂—C≡CH.

The term “C_(2-n)-alkynylene” is used for a group as defined in thedefinition for “C_(1-n)-alkylene” with at least two carbon atoms, if atleast two of those carbon atoms of said group are bonded to each otherby a triple bond. For example the term C₂₋₃-alkynylene includes —C≡C—,—C≡C—CH₂—, —CH₂—C≡C—.

The term “C_(3-n)-carbocyclyl” as used either alone or in combinationwith another radical, denotes a monocyclic, bicyclic or tricyclic,saturated or unsaturated hydrocarbon radical with 3 to n C atoms. Thehydrocarbon radical is preferably nonaromatic. Preferably the 3 to n Catoms form one or two rings. In case of a bicyclic or tricyclic ringsystem the rings may be attached to each other via a single bond or maybe fused or may form a spirocyclic or bridged ring system. For examplethe term C₃₋₁₀-carbocyclyl includes C₃₋₁₀-cycloalkyl,C₃₋₁₀-cycloalkenyl, octahydropentalenyl, octahydroindenyl,decahydronaphthyl, indanyl, tetrahydronaphthyl. Most preferably the termC_(3-n)-carbocyclyl denotes C_(3-n)-cycloalkyl, in particularC₃₋₇-cycloalkyl.

The term “C_(3-n)-cycloalkyl”, wherein n is an integer 4 to n, eitheralone or in combination with another radical denotes a cyclic,saturated, unbranched hydrocarbon radical with 3 to n C atoms. Thecyclic group may be mono-, bi-, tri- or spirocyclic, most preferablymonocyclic. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclododecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl,norpinyl, norbonyl, norcaryl, adamantyl, etc.

The term “C_(3-n)-cycloalkenyl”, wherein n is an integer 3 to n, eitheralone or in combination with another radical, denotes a cyclic,unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to nC atoms, at least two of which are bonded to each other by a doublebond. For example the term C₃₋₇-cycloalkenyl includes cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,cyclohexadienyl, cycloheptenyl, cycloheptadienyl and cycloheptatrienyl.

The term “aryl” as used herein, either alone or in combination withanother radical, denotes a carbocyclic aromatic monocyclic groupcontaining 6 carbon atoms which may be further fused to a second 5- or6-membered carbocyclic group which may be aromatic, saturated orunsaturated. Aryl includes, but is not limited to, phenyl, indanyl,indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl anddihydronaphthyl. More preferably the term “aryl” as used herein, eitheralone or in combination with another radical, denotes phenyl ornaphthyl, most preferably phenyl.

The term “heterocyclyl” means a saturated or unsaturated mono-, bi-,tri- or spirocarbocyclic, preferably mono-, bi- or spirocyclic-ringsystem containing one or more heteroatoms selected from N, O or S(O)_(r)with r=0, 1 or 2, which in addition may have a carbonyl group. Morepreferably the term “heterocyclyl” as used herein, either alone or incombination with another radical, means a saturated or unsaturated, evenmore preferably a saturated mono-, bi- or spirocyclic-ring systemcontaining 1, 2, 3 or 4 heteroatoms selected from N, O or S(O)_(r) withr=0, 1 or 2 which in addition may have a carbonyl group. The term“heterocyclyl” is intended to include all the possible isomeric forms.Examples of such groups include aziridinyl, oxiranyl, azetidinyl,oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl,tetrahydropyranyl, azepanyl, piperazinyl, morpholinyl,tetrahydrofuranonyl, tetrahydropyranonyl, pyrrolidinonyl, piperidinonyl,piperazinonyl, morpholinonyl.

Thus, the term “heterocyclyl” includes the following exemplarystructures which are not depicted as radicals as each form may beattached through a covalent bond to any atom so long as appropriatevalences are maintained:

The term “heteroaryl” means a mono- or polycyclic, preferably mono- orbicyclic-ring system containing one or more heteroatoms selected from N,O or S(O)_(r) with r=0, 1 or 2 wherein at least one of the heteroatomsis part of an aromatic ring, and wherein said ring system may have acarbonyl group. More preferably the term “heteroaryl” as used herein,either alone or in combination with another radical, means a mono- orbicyclic-ring system containing 1, 2, 3 or 4 heteroatoms selected fromN, O or S(O)_(r) with r=0, 1 or 2 wherein at least one of theheteroatoms is part of an aromatic ring, and wherein said ring systemmay have a carbonyl group. The term “heteroaryl” is intended to includeall the possible isomeric forms.

Thus, the term “heteroaryl” includes the following exemplary structureswhich are not depicted as radicals as each form may be attached througha covalent bond to any atom so long as appropriate valences aremaintained:

Many of the terms given above may be used repeatedly in the definitionof a formula or group and in each case have one of the meanings givenabove, independently of one another.

Pharmacological Activity

The activity of the compounds of the invention may be demonstrated usingthe following assay:

The compounds of formula I according to the invention modulate theactivity of the G-protein-coupled receptor GPR119. The effect of thecompounds on the activation of GPR119 and on the stimulation ofintracellular cAMP concentration is determined using the AlphaScreencAMP Assay Kit (Cat. No. #6760625R) made by PerkinElmer.

MIN6 cells [Miyazaki J et al., Endocrinology. 1990 July; 127(1):126-32]are stably transfected with an expression vector for human GPR119 cDNA(Acc. No. NP_(—)848566). Min-6/hGPR119 cells are cultured in DMEM, 10%FBS, 50 μM β-mercaptoethanol, 0.3 mg/mL Geniticin, 2 mM GlutaMAX at 37°C., 5% CO₂. For the assay, the cells are seeded in Optiplates (white,384-well, 160W-barcoded, TC, sterile with lid, Cat. No. #6007688 (PerkinElmer); 10000 cells/well; 50 μL). The plates covered with lids are thenincubated for 24 hours at 37° C., 5% CO₂. After the medium is aspiratedfrom the wells completely, 10 μl of the test compound are added, thecompounds are diluted using stimulating buffer (140 mM NaCl, 3.6 mM KCl,0.5 mM NaH₂PO₄, 0.5 mM MgSO₄, 1.5 mM CaCl₂, 10 mM Hepes, 5 mM NaHCO₃; pH7.4. 0.5 mM IBMX and 0.1% BSA, the final DMSO concentration is 1%).After 45 minutes incubation at room temperature (approx. 20° C.), thecAMP concentrations are determined using the AlphaScreen cAMP Assay Kit(Cat. No. #6760625R from PerkinElmer). 10 μl of Biotin-cAMP (finalconcentration 1 U/well in lysing buffer (5 mM Hepes (pH 7.4), 0.1% BSA,0.5% Tween) and 10 μL Bead solution (final concentration 1 U/well inlysing buffer) are added. The plates are incubated for another 2 hoursat room temperature. The cAMP concentrations are calculated using a cAMPstandard curve from the Alpha Screen Counts. The data analysis iscarried out by calculating the EC₅₀ value and the maximum value based ona positive control, using suitable software (Graphpad Prism). Thecompounds according to the invention increase the intracellular cAMPlevel in the range of 3-5.

The compounds according to the invention typically have EC₅₀ values inthe range from about 1 nM to about 10 μM, preferably less than 1 μM,more preferably less than 100 nM.

EC₅₀ values for compounds according to the invention are shown in thefollowing Table. The number of the compound corresponds to the number ofthe Example in the experimental section.

Exam- EC₅₀ Exam- EC₅₀ Exam- EC₅₀ Exam- EC₅₀ ple [nM] ple [nM] ple [nM]ple [nM] 1 58 2 62 3 9 4 121 5 263 6 45 7 108 8 281 9 567 10 592 11 31012 105 13 82 14 9 15 233 16 64 17 51 18 79 19 12 20 13 21 19 22 10 23 8624 28 25 41 26 18 27 140 28 73

In view of their ability to modulate the activity of theG-protein-coupled receptor GPR119, in particular an agonistic activity,the compounds of general formula I according to the invention, includingthe compounds I-a, I-b, and I-c, including the corresponding saltsthereof, are suitable for the treatment of diseases or conditions whichmay be affected or which are mediated by the activation of theG-protein-coupled receptor GPR119.

Accordingly, the present invention relates to a compound of generalformula I including the compounds I-a, I-b, and I-c as a medicament.

Furthermore, the present invention relates to the use of a compound ofgeneral formula I including the compounds I-a, I-b, and I-c or apharmaceutical composition according to this invention for the treatmentand/or prevention of diseases or conditions which are mediated by theactivation of the G-protein-coupled receptor GPR119 in a patient,preferably in a human.

In yet another aspect the present invention relates to a method fortreating a disease or condition mediated by the activation of theG-protein-coupled receptor GPR119 in a mammal that includes the step ofadministering to a patient, preferably a human, in need of suchtreatment a therapeutically effective amount of a compound or apharmaceutical composition of the present invention including thecompounds I-a, I-b, and I-c.

Diseases and conditions mediated by agonists of the G-protein-coupledreceptor GPR119 embrace metabolic diseases or conditions.

According to one aspect the compounds and pharmaceutical compositions ofthe present invention including the compounds I-a, I-b, and I-c areparticularly suitable for treating diabetes mellitus, in particular Type2 diabetes, Type 1 diabetes, complications of diabetes (such as e.g.retinopathy, nephropathy or neuropathies, diabetic foot, ulcers ormacroangiopathies), metabolic acidosis or ketosis, reactivehypoglycaemia, hyperinsulinaemia, glucose metabolic disorder, insulinresistance, metabolic syndrome, dyslipidaemias of different origins,atherosclerosis and related diseases, obesity, high blood pressure,chronic heart failure, oedema and hyperuricaemia.

The compounds and pharmaceutical compositions of the present inventionincluding the compounds I-a, I-b, and I-c are also suitable forpreventing beta-cell degeneration such as e.g. apoptosis or necrosis ofpancreatic beta cells. The compounds and pharmaceutical compositions ofthe present invention are also suitable for improving or restoring thefunctionality of pancreatic cells, and also for increasing the numberand size of pancreatic beta cells.

Therefore according to another aspect the invention relates to compoundsof formula I including the compounds I-a, I-b, and I-c andpharmaceutical compositions according to the invention for use inpreventing, delaying, slowing the progression of and/or treatingmetabolic diseases, particularly in improving the glycaemic controland/or beta cell function in the patient.

In another aspect the invention relates to compounds of formula Iincluding the compounds I-a, I-b, and I-c and pharmaceuticalcompositions according to the invention for use in preventing, delaying,slowing the progression of and/or treating type 2 diabetes, overweight,obesity, complications of diabetes and associated pathologicalconditions.

In addition the compounds and pharmaceutical compositions according tothe invention including the compounds I-a, I-b, and I-c are suitable foruse in one or more of the following therapeutic processes:

-   -   for preventing, delaying, slowing the progression of or treating        metabolic diseases, such as for example type 1 diabetes, type 2        diabetes, insufficient glucose tolerance, insulin resistance,        hyperglycaemia, hyperlipidaemia, hypercholesterolaemia,        dyslipidaemia, syndrome X, metabolic syndrome, obesity, high        blood pressure, chronic systemic inflammation, retinopathy,        neuropathy, nephropathy, atherosclerosis, endothelial        dysfunction or bone-related diseases (such as osteoporosis,        rheumatoid arthritis or osteoarthritis);    -   for improving glycaemic control and/or reducing fasting plasma        glucose, postprandial plasma glucose and/or the glycosylated        haemoglobin HbA1c;    -   for preventing, delaying, slowing or reversing the progression        of disrupted glucose tolerance, insulin resistance and/or        metabolic syndrome to type 2 diabetes;    -   for preventing, delaying, slowing the progression of or treating        a condition or a disease selected from among the complications        of diabetes, such as for example retinopathy, nephropathy or        neuropathies, diabetic foot, ulcers or macroangiopathies;    -   for reducing weight or preventing weight gain or assisting        weight loss;    -   for preventing or treating the degradation of pancreatic beta        cells and/or improving and/or restoring the functionality of        pancreatic beta cells and/or restoring the functionality of        pancreatic insulin secretion;    -   for maintaining and/or improving insulin sensitivity and/or        preventing or treating hyperinsulinaemia and/or insulin        resistance.

In particular, the compounds and pharmaceutical compositions accordingto the invention including the compounds I-a, I-b, and I-c are suitablefor the treatment of obesity, diabetes (comprising type 1 and type 2diabetes, preferably type 2 diabetes mellitus) and/or complications ofdiabetes (such as for example retinopathy, nephropathy or neuropathies,diabetic foot, ulcers or macroangiopathies).

The compounds according to the invention including the compounds I-a,I-b, and I-c are most particularly suitable for treating type 2 diabetesmellitus.

The dose range of the compounds of general formula I, including thecompounds I-a, I-b, and I-c, applicable per day is usually from 0.001 to10 mg per kg body weight, for example from 0.01 to 8 mg per kg bodyweight of the patient. Each dosage unit may conveniently contain from0.1 to 1000 mg, for example 0.5 to 500 mg.

The actual therapeutically effective amount or therapeutic dosage willof course depend on factors known to those skilled in the art such asage and weight of the patient, route of administration and severity ofdisease. In any case the compound or composition will be administered atdosages and in a manner which allows a therapeutically effective amountto be delivered based upon patient's unique condition.

The compounds, compositions, including any combinations with one or moreadditional therapeutic agents, according to the invention may beadministered by oral, transdermal, inhalative, parenteral or sublingualroute. Of the possible methods of administration, oral or intravenousadministration is preferred.

Pharmaceutical Compositions

Suitable preparations for administering the compounds of formula I,including the compounds I-a, I-b, and I-c, optionally in combinationwith one or more further therapeutic agents, will be apparent to thoseskilled in the art and include for example tablets, pills, capsules,suppositories, lozenges, troches, solutions, syrups, elixirs, sachets,injectables, inhalatives and powders etc. Oral formulations,particularly solid forms such as e.g. tablets or capsules are preferred.The content of the pharmaceutically active compound(s) is advantageouslyin the range from 0.1 to 90 wt.-%, for example from 1 to 70 wt.-% of thecomposition as a whole.

Suitable tablets may be obtained, for example, by mixing one or morecompounds according to formula I, including the compounds I-a, I-b, andI-c, with known excipients, for example inert diluents, carriers,disintegrants, adjuvants, surfactants, binders and/or lubricants. Thetablets may also consist of several layers. The particular excipients,carriers and/or diluents that are suitable for the desired preparationswill be familiar to a person skilled in the art on the basis of hisspecialist knowledge. The preferred ones are those that are suitable forthe particular formulation and method of administration that aredesired. The preparations or formulations according to the invention maybe prepared using methods known per se that are familiar to a personskilled in the art, such as for example by mixing or combining at leastone compound of formula I according to the invention, or apharmaceutically acceptable salt of such a compound, and one or moreexcipients, carriers and/or diluents.

Combination Therapy

The compounds of the invention including the compounds I-a, I-b, and I-cmay further be combined with one or more, preferably one additionaltherapeutic agent. According to one embodiment the additionaltherapeutic agent is selected from the group of therapeutic agentsuseful in the treatment of diseases or conditions describedhereinbefore, in particular associated with metabolic diseases orconditions such as for example diabetes mellitus, obesity, diabeticcomplications, hypertension, hyperlipidemia. Additional therapeuticagents which are suitable for such combinations include in particularthose which for example potentiate the therapeutic effect of one or moreactive substances with respect to one of the indications mentionedand/or which allow the dosage of one or more active substances to bereduced.

Therefore a compound of the invention including the compounds I-a, I-b,and I-c may be combined with one or more additional therapeutic agentsselected from the group consisting of antidiabetic agents, agents forthe treatment of overweight and/or obesity and agents for the treatmentof high blood pressure, heart failure and/or atherosclerosis.

Antidiabetic agents are for example metformin, sulphonylureas,nateglinide, repaglinide, thiazolidinediones, PPAR-(alpha, gamma oralpha/gamma) agonists or modulators, alpha-glucosidase inhibitors, DPPIVinhibitors, SGLT2-inhibitors, insulin and insulin analogues, GLP-1 andGLP-1 analogues or amylin and amylin analogues, cycloset, 11β-HSDinhibitors. Other suitable combination partners are inhibitors ofprotein tyrosinephosphatase 1, substances that affect deregulatedglucose production in the liver, such as e.g. inhibitors ofglucose-6-phosphatase, or fructose-1,6-bisphosphatase, glycogenphosphorylase, glucagon receptor antagonists and inhibitors ofphosphoenol pyruvate carboxykinase, glycogen synthase kinase or pyruvatedehydrokinase, alpha2-antagonists, CCR-2 antagonists or glucokinaseactivators. One or more lipid lowering agents are also suitable ascombination partners, such as for example HMG-CoA-reductase inhibitors,fibrates, nicotinic acid and the derivatives thereof, PPAR-(alpha, gammaor alpha/gamma) agonists or modulators, PPAR-delta agonists, ACATinhibitors or cholesterol absorption inhibitors such as, bileacid-binding substances such as, inhibitors of ileac bile acidtransport, MTP inhibitors, or HDL-raising compounds such as CETPinhibitors or ABC1 regulators.

Therapeutic agents for the treatment of overweight and/or obesity arefor example antagonists of the cannabinoid1 receptor, MCH-1 receptorantagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists,β3-agonists, leptin or leptin mimetics, agonists of the 5HT2c receptor.

Therapeutic agents for the treatment of high blood pressure, chronicheart failure and/or atherosclerosis are for example A-II antagonists orACE inhibitors, ECE inhibitors, diuretics, β-blockers, Ca-antagonists,centrally acting antihypertensives, antagonists of thealpha-2-adrenergic receptor, inhibitors of neutral endopeptidase,thrombocyte aggregation inhibitors and others or combinations thereofare suitable. Angiotensin II receptor antagonists are preferably usedfor the treatment or prevention of high blood pressure and complicationsof diabetes, often combined with a diuretic such as hydrochlorothiazide.

The dosage for the combination partners mentioned above is usually ⅕ ofthe lowest dose normally recommended up to 1/1 of the normallyrecommended dose.

Preferably, compounds of the present invention including the compoundsI-a, I-b, and I-c and/or pharmaceutical compositions comprising acompound of the present invention optionally in combination with one ormore additional therapeutic agents are administered in conjunction withexercise and/or a diet.

Therefore, in another aspect, this invention relates to the use of acompound according to the invention including the compounds I-a, I-b,and I-c in combination with one or more additional therapeutic agentsdescribed hereinbefore and hereinafter for the treatment of diseases orconditions which may be affected or which are mediated by the activationof the G-protein-coupled receptor GPR119, in particular diseases orconditions as described hereinbefore and hereinafter.

In yet another aspect the present invention relates to a method fortreating a disease or condition mediated by the activation of theG-protein-coupled receptor GPR119 in a patient that includes the step ofadministering to the patient, preferably a human, in need of suchtreatment a therapeutically effective amount of a compound of thepresent invention including the compounds I-a, I-b, and I-c incombination with a therapeutically effective amount of one or moreadditional therapeutic agents described in hereinbefore and hereinafter.

The use of the compound according to the invention including thecompounds I-a, I-b, and I-c in combination with the additionaltherapeutic agent may take place simultaneously or at staggered times.

The compound according to the invention including the compounds I-a,I-b, and I-c and the one or more additional therapeutic agents may bothbe present together in one formulation, for example a tablet or capsule,or separately in two identical or different formulations, for example asa so-called kit-of-parts.

Consequently, in another aspect, this invention relates to apharmaceutical composition which comprises a compound according to theinvention including the compounds I-a, I-b, and I-c and one or moreadditional therapeutic agents described hereinbefore and hereinafter,optionally together with one or more inert carriers and/or diluents.

Other features and advantages of the present invention will becomeapparent from the following more detailed Examples which illustrate, byway of example, the principles of the invention.

EXAMPLES

The terms “ambient temperature” and “room temperature” are usedinterchangeably and designate a temperature of about 20° C.

Preliminary Remarks:

As a rule, ¹H-NMR and/or mass spectra have been obtained for thecompounds prepared. The R_(f) values are determined using Merck silicagel 60 F₂₅₄ plates and UV light at 254 nm.

Parameters of analytical HPLC employed for characterization of products(TFA denotes trifluoroacetic acid):

Method: 1 Device: Agilent 1200 with DA and MS detector Column: XBridgeC18, 3 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ Solvent %Solvent % Solvent Flow Temperature Time [min] [H₂O, 0.1% TFA] [Methanol][ml/min] [° C.] 0.0  95 5 2.2 60 0.05 95 5 2.2 60 1.40 0 100 2.2 60 1.800 100 2.2 60

Method: 2 Device: Waters Alliance with DA and MS detector Column:XBridge C18, 4.6 × 30 mm, 3.5 μm Column Supplier: Waters Gradient/Solvent % Solvent % Solvent Flow Temperature Time [min] [H₂O, 0.1% TFA][Methanol] [ml/min] [° C.] 0.0 95 5 4.8 60 1.6 0 100 4.8 60  1.85 0 1004.8 60 1.9 95 5 4.8 60

Method: 3 Device: Waters Alliance with DA and MS detector Column:XBridge C18, 4.6 × 30 mm, 3.5 μm Column Supplier: Waters Gradient/Solvent % Solvent % Solvent Flow Temperature Time [min] [H₂O, 0.1% TFA][Methanol] [ml/min] [° C.] 0.0 95 5 4 60 1.6 0 100 4 60  1.85 0 100 4 601.9 95 5 4 60

Method: 4 Device: Agilent 1100 with DA and MS detector Column: XBridgeC18, 4.6 × 30 mm, 3.5 μm Column Supplier: Waters Gradient/ % SolventSolvent [H₂O, % Solvent Flow Temperature Time [min] 0.1% HCOOH][Methanol] [ml/min] [° C.] 0.0  95 5 4 60 0.15 95 5 4 60 1.7  0 100 4 602.25 0 100 4 60

Method: 5 Device: Agilent 1200 with DA and MS detector Column: XBridgeC18, 3 × 30 mm, 2.5 μm Column Supplier: Waters Gradient/ Solvent %Solvent % Solvent Flow Temperature Time [min] [H₂O, 0.1% NH₃] [Methanol][ml/min] [° C.] 0.0  95 5 2.2 60 0.05 95 5 2.2 60 1.40 0 100 2.2 60 1.800 100 2.2 60

Method: 6 Device: Agilent 1100 with DA and MS detector Column: XBridgeC18, 4.6 × 30 mm, 3.5 μm Column Supplier: Waters Gradient/ Solvent %Solvent % Solvent Flow Temperature Time [min] [H₂O, 0.1% NH₃] [Methanol][ml/min] [° C.] 0.0  95 5 4 60 0.15 95 5 4 60 1.7  0 100 4 60 2.25 0 1004 60

Intermediate 14-(5-Chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester

Copper(I) iodide (25 mg) andbis-(triphenylphosphine)-palladium(II)-chloride (30 mg) are added to6-chloro-4-iodo-pyridin-3-ol (200 mg) in N,N-dimethylformamide (3 mL)under Ar atmosphere at room temperature. Triethylamine (110 μL) is addedand the resulting mixture is stirred at room temperature for 1 h.4-Ethynyl-piperidine-1-carboxylic acid tert-butyl ester (175 mg)dissolved in N,N-dimethylformamide (2 mL) is added dropwise and themixture is stirred at 55° C. for 3 h. The solvent is evaporated and theresidue is chromatographed on silica gel (cyclohexane/ethyl acetate70:30) to give the title compound. LC (method 2): t_(R)=1.40 min; Massspectrum (ESI⁺): m/z=337/339 (Cl) [M+H]⁺.

Intermediate 24-(2,5-Dichloro-pyridin-4-ylethynyl)-piperidine-1-carboxylic acidtert-butyl ester

Copper(I) iodide (0.50 g), bis-(triphenylphosphine)-palladium(II)chloride (0.50 g), and triethylamine (3.4 mL) are added successively toa solution of 2,5-dichloro-4-iodo-pyridine (6.54 g) inN,N-dimethylformamide (45 mL) under Ar atmosphere at room temperature.The resulting mixture is stirred at room temperature for 1 h prior tothe addition of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester(5.15 g). The mixture is stirred at 55° C. for 2 h. The solvent isevaporated and the residue is diluted with ethyl acetate. The resultingmixture is washed with water and brine, dried (Na₂SO₄), andconcentrated. The residue is chromatographed on silica gel(cyclohexane/ethyl acetate 85:15→50:50) to give the title compound. LC(method 3): t_(R)=1.66 min; Mass spectrum (ESI⁺): m/z=355/357/359 (2 Cl)[M+H]⁺.

Intermediate 34-[5-Chloro-2-(4-cyano-2-fluoro-phenyl)-pyridin-4-ylethynyl]-piperidine-1-carboxylicacid tert-butyl ester

A flask charged with a stir bar,4-(2,5-dichloro-pyridin-4-ylethynyl)-piperidine-1-carboxylic acidtert-butyl ester (0.30 g), 4-cyano-2-fluoro-phenylboronic acid (0.20 g),2 M aqueous Na₂CO₃ solution (1 mL), and 1,4-dioxane (3 mL) is spargedwith Ar for 10 min. Tetrakis(triphenylphosphine)palladium(0) (40 mg) isadded and the resulting mixture is stirred in a microwave over at 160°C. for 45 min. After cooling to room temperature, water is added and theresulting mixture is extracted with ethyl acetate.

The combined extracts are washed with brine, dried (Na₂SO₄), andconcentrated. The residue is chromatographed on silica gel(cyclohexane/ethyl acetate 85:15) to give the title compound. LC (method3): t_(R)=1.70 min; Mass spectrum (ESI⁺): m/z=440/442 (Cl) [M+H]⁺.

Intermediate 44-[5-(2-Triisopropylsilanyl-oxazol-5-yl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

A mixture of4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester (0.20 g),5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-triisopropylsilanyl-oxazole(0.35 g), 2 M aqueous Na₂CO₃ solution (0.8 mL), andN,N-dimethylformamide (3 mL) is sparged with argon for 10 min.PdCl_(2[)1,1′-bis(diphenylphosphino)-ferrocene]*CH₂Cl₂ complex (0.15 g)is added and the mixture is stirred at 80° C. overnight. The mixture isconcentrated, diluted with water and methanol, and purified by HPLC onreversed phase (methanol/water) to give the title compound. LC (method4): t_(R)=2.07 min; Mass spectrum (ESI⁺): m/z=526 [m+H]⁺.

Intermediate 55-(2-Fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine

Trifluoroacetic acid (1.2 mL) is added to4-[5-(2-fluoro-4-methanesulfonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (0.78 g) in dichloromethane (14 mL). The mixtureis stirred at room temperature overnight. Aqueous NaHCO₃ solution isadded, the resulting mixture is stirred for 5 min, and the phases areseparated. The aqueous phase is extracted with dichloromethane and thecombined organic phases are washed with water and dried (Na₂SO₄). Thesolvent is evaporated to give the title compound. LC (method 1):t_(R)=0.59 min; Mass spectrum (ESI⁺): m/z=375 [M+H]⁺.

Intermediate 61-{4-[5-(2-Fluoro-4-methanesulfonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidin-1-yl}-2-methyl-propan-2-ol

1,1-Dimethyloxirane (55 μL) is added to a solution of5-(2-fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine(0.15 g) in methanol (2 mL) and dichloromethane (3 mL) at roomtemperature. The solution is stirred at 50° C. overnight. The solutionis concentrated to give the crude title compound that is used withoutfurther purification. LC (method 4): t_(R)=0.98 min; Mass spectrum(ESI⁺): m/z=447 [M+H]⁺.

Intermediate 75-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridine

The title compound is prepared from4-[5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester following a procedure analogous to that describedfor Intermediate 5.

Intermediate 84-(5-Chloro-furo[2,3-c]pyridin-2-yl)-4-methyl-piperidine-1-carboxylicacid tert-butyl ester

Step 1: 4-formyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester

Potassium tert-butoxide (2.80 g) and methyl iodide (3.60 mL) are addedto an ice cold solution of 4-formyl-piperidine-1-carboxylic acidtert-butyl ester (4.00 g) in dichloromethane (24 mL). The mixture isstirred in the cooling bath for 30 min and then at room temperatureovernight. Brine is added and the resulting mixture is extracted withdichloromethane. The combined extracts are dried (MgSO₄) andconcentrated to give the crude title compound that is used withoutfurther purification.

Step 2: 4-ethynyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester

K₂CO₃ (5.25 g) and 4-formyl-4-methyl-piperidine-1-carboxylic acidtert-butyl ester (5.23 g) are added to an ice cold mixture of dimethyl(1-diazo-2-oxopropyl)-phosphonate (5.50 g), molecular sieves (2 g), andmethanol (30 mL). The mixture is stirred in the cooling bath for 30 minand then at room temperature overnight. The mixture is filtered andaqueous NH₄Cl solution is added to the filtrate. The resulting mixtureis extracted with dichloromethane and the combined extracts areconcentrated. The residue is chromatographed on silica gel(cyclohexane/ethyl acetate 4:1→1:1) to give the title compound.

Step 3:4-(5-chloro-furo[2,3-c]pyridin-2-yl)-4-methyl-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from4-ethynyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester and2-chloro-5-hydroxy-4-iodo-pyridine following a procedure analogous tothat described for Intermediate 5. LC (method 4): t_(R)=1.76 min; Massspectrum (ESI⁺): m/z=351/353 (Cl) [M+H]⁺.

Example 14-[5-(4-Methanesulfonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

A mixture of4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester (390 mg), 4-(methanesulfonyl)phenyl boronic acid (350mg), 2 M aqueous Na₂CO₃ solution (1.50 mL), and 1,4-dioxane (10 mL) issparged with Ar for 10 min. Pd(PPh₃)₄ (100 mg) is added and theresulting mixture is stirred at 170° C. for 1 h in a microwave oven. Thereaction mixture is concentrated, diluted with water, and extracted withethyl acetate. The combined extracts are washed with brine, dried(MgSO₄), and concentrated. The residue is chromatographed on silica gel(cyclohexane/ethyl acetate 60:40→40:60) to give the title compound. LC(method 2): t_(R)=1.23 min; Mass spectrum (ESI⁺): m/z=457 [M+H]⁺.

Example 24-[5-(3-Fluoro-4-methanesulfonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester and 3-fluoro-4-methylsulfonyl-phenylboronic acidfollowing a procedure analogous to that described for Example 1. LC(method 4): t_(R)=1.71 min; Mass spectrum (ESI⁺): m/z=475 [M+H]⁺.

Example 34-[5-(2-Fluoro-4-methanesulfonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

A mixture of4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester (100 mg), 2-fluoro-4-(methanesulfonyl)phenylboronicacid (97 mg), 2 M aqueous Na₂CO₃ solution (0.33 mL), methanol (0.5 mL),and 1,4-dioxane (1.5 mL) is sparged with Ar for 10 min. PdCl₂[1,1′-bis(diphenylphosphino)-ferrocene]*CH₂Cl₂ complex (22 mg) is addedand the mixture is stirred at reflux temperature for 2 h. The mixture isdiluted with water and methanol and purified by HPLC on reversed phase(methanol/water) to give the title compound. LC (method 5): t_(R)=1.29min; Mass spectrum (ESI⁺): m/z=475 [M+H]⁺.

Example 44-[5-(4-Methanesulfonylamino-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester and 4-methylsulfonylamino-phenylboronic acid followinga procedure analogous to that described for Example 1. LC (method 4):t_(R)=1.57 min; Mass spectrum (ESI⁺): m/z=472 [M+H]⁺.

Example 54-[5-(4-Cyano-3-fluoro-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester and 4-cyano-3-fluoro-phenylboronic acid following aprocedure analogous to that described for Example 1; the reaction isconducted at 150° C. LC (method 4): t_(R)=1.84 min; Mass spectrum(ESI⁺): m/z=422 [M+H]⁺.

Example 64-[5-(4-Ethylcarbamoyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester and 4-ethylcarbamoyl-phenylboronic acid following aprocedure analogous to that described for Example 1; the reaction isconducted at 150° C. LC (method 4): t_(R)=1.68 min; Mass spectrum(ESI⁺): m/z=450 [M+H]⁺.

Example 74-[5-(2-Fluoro-4-aminocarbonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

A flask is charged under Ar atmosphere with a stir bar,4-[5-chloro-2-(4-cyano-2-fluoro-phenyl)-pyridin-4-ylethynyl]-piperidine-1-carboxylicacid tert-butyl ester (110 mg), powdered KOH (42 mg),2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (8 mg),tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (6 mg), water(1.5 mL), and 1,4-dioxane (3 mL). The mixture is heated to 110° C. andstirred at this temperature for 2 h. After cooling the mixture to roomtemperature, water is added and the resulting mixture is extracted withethyl acetate. The combined extracts are washed with brine, dried(Na₂SO₄), and concentrated. The residue is chromatographed on silica gel[dichloromethane/(dichloromethane/methanol/7 M ammonia in methanol50:48:2) 9:1] to give the title compound. LC (method 3): t_(R)=1.26 min;Mass spectrum (ESI⁺): m/z=440 [M+H]⁺.

Example 84-[5-(4-Cyano-2-fluoro-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

Trifluoroacetic anhydride (26 μL) is added to a solution of4-[5-(2-fluoro-4-aminocarbonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (40 mg) and triethylamine (51 μL) indichloromethane (3 mL) at room temperature. The solution is stirred atroom temperature for 2 h before another portion of trifluoroaceticanhydride (26 μL) and triethylamine (51 μL) is added. The solution isstirred for 0.5 h and then aqueous NaHCO₃ solution is added. Theresulting mixture is extracted with dichloromethane and the combinedextracts are washed with brine, dried (Na₂SO₄), and concentrated. Theresidue is triturated with ether and then with methanol to give thetitle compound. LC (method 3): t_(R)=1.52 min; Mass spectrum (ESI⁺):m/z=422 [M+H]⁺.

Example 94-[5-(4-Benzyloxycarbonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester and 4-benzyloxycarbonyl-phenylboronic acid following aprocedure analogous to that described for Example 1; the reaction isconducted at 150° C. Mass spectrum (ESI⁺): m/z=513 [M+H]⁺.

Example 104-(5-Oxazol-5-yl-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester

Tetrabutylammonium fluoride (1 mol/L in tetrahydrofuran; 1.5 mL) isadded to a solution of4-[5-(2-triisopropylsilanyl-oxazol-5-yl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (0.31 g) in tetrahydrofuran (6 mL) chilled in anice bath. The cooling bath is removed and the solution is stirred atroom temperature for 2 h. Water is added and the resulting mixture isextracted with ethyl acetate. The combined extracts are dried (Na₂SO₄)and concentrated. The residue is purified by HPLC on reversed phase(methanol/water) to give the title compound. LC (method 4): t_(R)=1.66min; Mass spectrum (ESI⁺): m/z=370 [M+H]⁺.

Example 114-(5-Pyridin-4-yl-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester

The title compound is prepared from4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester and pyridine-4-boronic acid following a procedureanalogous to that described for Example 1; the reaction is conducted at150° C. LC (method 1): t_(R)=1.31 min; Mass spectrum (ESI⁺): m/z=380[M+H]⁺.

Example 124-[5-(4-Methanesulfonylmethyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester and 4-methylsulfonylmethyl-phenylboronic acid followinga procedure analogous to that described for Example 1; the reaction isconducted at 150° C. LC (method 1): t_(R)=1.26 min; Mass spectrum(ESI⁺): m/z=471 [M+H]⁺.

Example 134-[5-(4-Methanesulfonyl-piperazin-1-yl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

4-(5-Chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester (80 mg) is added to a flask charged with a stir bar,N-methylsulfonyl-piperazine (47 mg), potassium tert-butoxide (63 mg),Xantphos (103 mg), tris(dibenzylideneacetone)-dipalladium(0) (54 mg),and toluene (3 mL). The mixture is sparged with Ar at room temperaturefor 10 min and then stirred at 110° C. overnight. After cooling themixture to room temperature, water is added and the resulting mixture isextracted with ethyl acetate. The combined extracts are dried (Na₂SO₄)and concentrated. The residue is purified by HPLC on reversed phase(methanol/water) to give the title compound. LC (method 5): t_(R)=1.25min; Mass spectrum (ESI⁺): m/z=465 [M+H]⁺.

Example 144-[5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester and1-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridinefollowing a procedure analogous to that described for Example 1; thereaction is conducted at 150° C. LC (method 1): t_(R)=1.27 min; Massspectrum (ESI⁺): m/z=462 [M+H]⁺.

Example 154-[5-(3-Fluoro-pyridin-4-yl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from4-(5-chloro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester and 3-fluoro-pyridine-4-boronic acid following aprocedure analogous to that described for Example 3. LC (method 5):t_(R)=1.32 min; Mass spectrum (ESI⁺): m/z=398 [M+H]⁺.

Example 162-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-yl]-5-(2-fluoro-4-methanesulfonyl-phenyl)-furo[2,3-c]pyridine

A mixture of5-(2-fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine(70 mg), 2-chloro-5-ethyl-pyrimidine (25 mg), N,N-diisopropyl-ethylamine(67 μL), and N,N-dimethylformamide (1 mL) is stirred at 120° C. for 4 hand then at 100° C. overnight. After cooling to room temperature, wateris added and the resulting mixture is extracted with ethyl acetate. Thecombined extracts are washed with brine, dried (Na₂SO₄), andconcentrated. The residue is chromatographed on silica gel(cyclohexane/ethyl acetate 4:1→1:1) to give the title compound. LC(method 1): t_(R)=1.18 min; Mass spectrum (ESI⁺): m/z=481 [M+H]⁺.

Example 175-(2-Fluoro-4-methanesulfonyl-phenyl)-2-[1-(1-trifluoromethyl-cyclopropylmethyl)-piperidin-4-yl]-furo[2,3-c]pyridine

A mixture of5-(2-fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine(80 mg), methanesulfonic acid 1-trifluoromethyl-cyclopropylmethyl ester(120 mg), KI (21 mg), K₂CO₃ (92 mg), and N-methylpyrrolidinone (3 mL) isstirred at 100° C. for 4 h. After cooling to room temperature, water isadded and the mixture is extracted with ethyl acetate. The combinedextracts are dried (Na₂SO₄) and concentrated. The residue ischromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:1) togive the title compound. Mass spectrum (ESI⁺): m/z=497 [M+H]⁺.

Example 185-(2-Fluoro-4-methanesulfonyl-phenyl)-2-[1-(2-fluoro-2-methyl-propyl)-piperidin-4-yl]-furo[2,3-c]pyridine

Bis(2-methoxyethyl)aminosulfur trifluoride (50% in toluene; 0.27 mL) isadded to a solution of5-(2-fluoro-4-methanesulfonyl-phenyl)-2-[1-(2-hydroxy-2-methyl-propyl)-piperidin-4-yl]-furo[2,3-c]pyridine(0.19 g) in dichloromethane (3 mL) chilled in an ice bath. The solutionis stirred at room temperature overnight. The solution is diluted withdichloromethane and little methanol and washed with aqueous NaHCO₃solution. The solution is dried (Na₂SO₄) and concentrated. The residueis chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→1:2) togive the title compound. LC (method 4): t_(R)=1.09 min; Mass spectrum(ESI⁺): m/z=449 [M+H]⁺.

Example 194-[5-(2-Fluoro-4-methanesulfonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid isopropyl ester

Isopropyl chloroformate (1 mol/L in toluene; 0.30 mL) is added to asolution of5-(2-fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine(75 mg) and N,N-diisopropyl-ethylamine (0.10 mL) in tetrahydrofuran (1mL) chilled in an ice bath. The solution is stirred at room temperaturefor 3 h. The solution is concentrated and the residue is taken up inwater and dichloromethane. The resulting mixture is extracted withdichloromethane and the combined extracts are dried (Na₂SO₄). Thesolvent is evaporated and the residue is purified by HPLC on reversedphase (methanol/water) to give the title compound. Mass spectrum (ESI⁺):m/z=461 [M+H]⁺.

Example 204-[5-(2-Fluoro-4-methanesulfonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid 1-methyl-cyclopropyl ester

1-Methyl-cyclopropyl 4-nitrophenyl carbonate (48 mg) is added to asolution of5-(2-fluoro-4-methanesulfonyl-phenyl)-2-piperidin-4-yl-furo[2,3-c]pyridine(75 mg) and N,N-diisopropyl-ethylamine (32 μL) in tetrahydrofuran (1 mL)at room temperature. The mixture is stirred at room temperatureovernight. The solution is concentrated and the residue is taken up inethyl acetate. The resulting mixture is washed with 1 M aqueous NaOHsolution (3×), water, and brine. The organic phase is dried (Na₂SO₄) andconcentrated. The residue is purified by HPLC on reversed phase(methanol/water) to give the title compound. Mass spectrum (ESI⁺):m/z=473 [M+H]⁺.

Example 214-[5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid isopropyl ester

The title compound is prepared from5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridineand isopropyl chloroformate following a procedure analogous to thatdescribed for Example 19. LC (method 6): t_(R)=1.45 min; Mass spectrum(ESI⁺): m/z=448 [M+H]⁺.

Example 224-[5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furo[2,3-c]pyridin-2-yl]-piperidine-1-carboxylicacid 1-methyl-cyclopropyl ester

The title compound is prepared from5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridineand 1-methyl-cyclopropyl 4-nitrophenyl carbonate following a procedureanalogous to that described for Example 20. Mass spectrum (ESI⁺):m/z=460 [M+H]⁺.

Example 234-[5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furo[2,3-c]pyridin-2-yl]-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl

A mixture of5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridine(50 mg), 2-chloro-5-trifluoromethyl-pyridine (25 mg), K₂CO₃ (40 mg), andN-methylpyrrolidinone (1 mL) is stirred at 60° C. overnight. Aftercooling to room temperature, water is added and the resulting mixture isextracted with ethyl acetate. The combined extracts are washed withbrine, dried (Na₂SO₄), and concentrated. The residue is chromatographedon silica gel (cyclohexane/ethyl acetate 4:1→1:2) to give the titlecompound. LC (method 1): t_(R)=1.05 min; Mass spectrum (ESI⁺): m/z=507[M+H]⁺.

Example 245-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-[1-(1-trifluoromethyl-cyclopropylmethyl)-piperidin-4-yl]-furo[2,3-c]pyridine

The title compound is prepared from5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridineand methanesulfonic acid 1-trifluoromethyl-cyclopropylmethyl esterfollowing a procedure analogous to that described for Example 17. LC(method 1): t_(R)=0.65 min; Mass spectrum (ESI⁺): m/z=484 [M+H]⁺.

Example 252-[1-(5-Chloro-pyrimidin-2-yl)-piperidin-4-yl]-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furo[2,3-c]pyridine

The title compound is prepared from5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridineand 2,5-dichloropyrimidine following a procedure analogous to thatdescribed for Example 23. LC (method 1): t_(R)=1.07 min; Mass spectrum(ESI⁺): m/z=474/476 (Cl) [M+H]⁺.

Example 265-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-[1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperidin-4-yl]-furo[2,3-c]pyridine

A mixture of5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-furo[2,3-c]pyridine(HCl salt, 70 mg), 2-chloro-5-trifluoromethyl-[1,3,4]thiadiazole (35mg), K₂CO₃ (55 mg), and dimethyl sulfoxide (3 mL) is stirred at 60° C.overnight. After cooling to room temperature, water is added and theresulting mixture is extracted with ethyl acetate. The combined extractsare washed with brine, dried (Na₂SO₄), and concentrated. The residue istriturated with methanol and then with diisopropylether to give thetitle compound. LC (method 1): t_(R)=0.94 min; Mass spectrum (ESI⁺):m/z=514 [M+H]⁺.

Example 274-[5-(4-Methanesulfonyl-phenyl)-furo[2,3-c]pyridin-2-yl]-4-methyl-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from4-(5-chloro-furo[2,3-c]pyridin-2-yl)-4-methyl-piperidine-1-carboxylicacid tert-butyl ester and 4-methanesulfonyl-phenylboronic acid followinga procedure analogous to that described for Example 1; the reaction isconducted at 150° C. LC (method 4): t_(R)=1.71 min; Mass spectrum(ESI⁺): m/z=471 [M+H]⁺.

Example 284-[5-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-furo[2,3-c]pyridin-2-yl]-4-methyl-piperidine-1-carboxylicacid tert-butyl ester

The title compound is prepared from4-(5-chloro-furo[2,3-c]pyridin-2-yl)-4-methyl-piperidine-1-carboxylicacid tert-butyl ester and1-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridinefollowing a procedure analogous to that described for Example 1; thereaction is conducted at 150° C. LC (method 4): t_(R)=1.58 min; Massspectrum (ESI⁺): m/z=476 [M+H]⁺.

The invention claimed is:
 1. A compound of formula I

wherein: R¹ is a group consisting of: a 5- or 6-membered heteroaromaticring which contains 1, 2, or 3 heteroatoms selected independently fromN, O, and S, and optionally substituted with a group R^(C) and/or one ormore substituents independently selected from L^(A); a groupC(═O)—O—R^(a), wherein R^(a) is C₁₋₆-alkyl optionally mono- orpolysubstituted with fluorine or C₃₋₆-cycloalkyl optionally mono- orpolysubstituted with fluorine and optionally substituted with CH₃, CF₃,or CHF₂; and a group CH₂—R^(b), wherein R^(b) is C₁₋₆-alkyl optionallymono- or polysubstituted with fluorine, or C₃₋₆-cycloalkyl optionallymono- or polysubstituted with fluorine and optionally substituted withCH₃, CF₃, or CHF₂; R² is H or C₁₋₃-alkyl; A is a group consisting of:1,2,3,6-tetrahydropyridin-4-yl and piperazin-1-yl, each substituted atthe N with a C₁₋₄-alkyl-S(═O)₂— group; and a phenyl ring and a 5- or6-membered heteroaromatic ring which contains 1, 2, or 3 heteroatomsselected independently from N, O, and S, each optionally substitutedwith a group T and optionally substituted with one or more substituentsindependently selected from L^(A); T is a group consisting of F, Cl, Br,I, CN, OH, NO₂, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl,C₁₋₆-alkyl-O—, C₃₋₆-cycloalkyl-O—, C₁₋₆-alkyl-S—, HO—C(═O)—,C₁₋₆-alkyl-O—C(═O)—, C₁₋₄-alkyl-C(═O)—, C₃₋₆-cycloalkyl-C(═O)—,C₁₋₄-alkyl-S(═O)₂—, R^(NT1)R^(NT2)N—, R^(NT1)R^(NT2)N—C(═O)—,R^(NT1)R^(NT2)N—S(═O)₂—, R^(NT1)R^(NT2)N—C(═O)—(R^(N))N—, heterocyclyl,heterocyclyl-O—, aryl, aryl-O—, heteroaryl, and heteroaryl-O—, wherein:each alkyl, alkenyl, alkynyl, and cycloalkyl group thereof is optionallysubstituted with one or more substituents independently selected from F,Cl, CN, OH, C₁₋₃-alkyl, C₃₋₆-cycloalkyl, C₁₋₃-alkyl-O—,R^(NT1)R^(NT2)N—, R^(NT1)R^(NT2)N—C(═O)—, C₁₋₄-alkyl-S(═O)—,C₁₋₄-alkyl-S(═O)₂—, R^(NT1)R^(NT2)N—S(═O)₂—, aryl, heteroaryl, orheterocyclyl, and heterocyclyl is a 4- to 7-membered unsaturated orsaturated carbocyclic ring in which 1 or 2-CH₂-groups independently ofeach other are replaced by NR^(N), O, —C(═O)—, S, —S(═O)—, or —S(═O)₂—,and/or in which a —CH-group is replaced by N; R^(N) is independently H,C₁₋₄-alkyl, C₁₋₄-alkyl-C(═O)—, or C₁₋₄-alkyl-S(═O)₂—; R^(NT1) is H,C₁₋₆-alkyl, C₃₋₆-cycloalkyl, C₁₋₆-alkyl-C(═O)—, C₁₋₆-alkyl-S(═O)₂,heterocyclyl, aryl, or heteroaryl, wherein: each alkyl and cycloalkylgroup thereof is optionally substituted with one or more substituentsindependently selected from F, OH, CN, C₁₋₄-alkyl, C₁₋₄-alkyl-O—, R^(N)₂N, C₁₋₄-alkyl-S(═O)₂—, C₃₋₆-cycloalkyl, heterocyclyl, phenyl, orheteroaryl, heterocyclyl is optionally substituted with one or moresubstituents independently selected from F, C₁₋₄-alkyl, R^(N) ₂N, OH, orC₁₋₄-alkyl-O—, heterocyclyl is a C₄₋₇-cycloalkyl ring in which 1 or2-CH₂-groups are independently replaced by NR^(N), O, C(═O), S, S(═O),or S(═O)₂, heteroaryl is a 5- or 6-membered aromatic ring which contains1, 2, or 3 heteroatoms independently selected from N, O, and S, whereinthe H-atom in one or more NH groups is replaced by R^(N), and R^(NT2) isH or C₁₋₆-alkyl; or R^(NT1) and R^(NT2) are linked to form one groupselected from a group consisting of a C₃₋₅-alkylene group, wherein 1 or2-CH₂-groups are independently replaced by NR^(N), O, C(═O), S, S(═O),or S(═O)₂, and which are optionally substituted with one or moresubstituents independently selected from F, C₁₋₄-alkyl, (R^(N))₂N, OH,or C₁₋₄-alkyl-O—; L^(A) is a group consisting of F, Cl, Br, CN, OH, NO₂,C₁₋₄-alkyl-O—, (R^(N))₂N—C(═O), (R^(N))₂N—, and C₁₋₄-alkyl-S(═O)₂—,wherein each alkyl group is optionally substituted with one or moresubstituents independently selected from F, Cl, CN, OH, orC₁₋₃-alkyl-O—; and R^(C) is a group consisting of F, Cl, Br, I, CN, OH,NO₂, C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₃₋₆-cycloalkyl,C₁₋₆-alkyl-O—, C₃₋₆-cycloalkyl-O—, C₁₋₆-alkyl-S—, HO—C(═O)—,C₁₋₆-alkyl-O—C(═O)—, C₁₋₄-alkyl-C(═O)—, C₃₋₆-cycloalkyl-C(═O)—,C₁₋₄-alkyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—, R^(NT1)R^(NT2)N—,R^(NT1)R^(NT2)N—C(═O)—, R^(NT1)R^(NT2)N—S(═O)₂—,R^(NT1)R^(NT2)N—C(═O)—(R^(N))N—, heterocyclyl, heterocyclyl-O—, aryl,aryl-O—, heteroaryl, and heteroaryl-O—, wherein: each alkyl, alkenyl,alkynyl, and cycloalkyl group is optionally substituted with one or moresubstituents independently selected from F, Cl, CN, OH, C₁₋₃-alkyl,C₃₋₆-cycloalkyl, C₁₋₃-alkyl-O—, R^(NT1)R^(NT2)N—,R^(NT1)R^(NT2)N—C(═O)—, C₁₋₄-alkyl-S(═O)—, C₁₋₄-alkyl-S(═O)₂—,R^(NT1)R^(NT2)N—S(═O)₂—, aryl, heteroaryl, or heterocyclyl, andheterocyclyl is a 4- to 7-membered unsaturated or saturated carbocyclicring in which 1 or 2-CH₂— groups are independently replaced by NR^(N),O, —C(═O)—, S, —S(═O)—, or —S(═O)₂—, and/or in which a —CH-group isreplaced by N; and wherein: aryl is phenyl or naphthyl, heteroaryl is a5- or 6-membered aromatic ring which contains 1, 2, 3, or 4 heteroatomsindependently selected from N, O, or S, wherein the H-atom in one ormore NH groups is optionally replaced by R^(N); and each aryl,heteroaryl, or heterocyclyl group is optionally substituted with one ormore substituents independently selected from L^(A), or a salt thereof.2. The compound according to claim 1, wherein the compound does notinclude the compounds I-a, I-b, and I-c:


3. The compound according to claim 1, wherein R¹ is selected from thegroup consisting of: a) a group selected from:

 wherein each ring is optionally substituted with one substituent R^(C),and b) a group selected from —C(═O)—O—(C₁₋₄-alkyl) and

 wherein each alkyl residue is optionally substituted with one or morefluorine atoms, and c) a group selected from


4. The compound according to claim 1, wherein A is selected from thegroup consisting of:

optionally additionally substituted with one or two F atoms, and b)


5. The compound according to claim 1, wherein T is —CN,C₁₋₄-alkyl-S(═O)₂—CH₂—, C₁₋₄-alkyl-S(═O)₂—, R^(NT1)R^(NT2)N—S(═O)₂—,R^(NT1)R^(NT2)N—C(═O)—, C₁₋₄-alkyl-S(═O)₂—(R^(N))N—, orR^(NT1)R^(NT2)N—.
 6. The compound according to claim 3, wherein T is—CN, C₁₋₄-alkyl-S(═O)₂—CH₂—, C₁₋₄-alkyl-S(═O)₂—,R^(NT1)R^(NT2)N—S(═O)₂—, R^(NT1)R^(NT2)N—C(═O)—,C₁₋₄-alkyl-S(═O)₂—(R^(N))N—, or R^(NT1)R^(NT2)N—.
 7. The compoundaccording to claim 4, wherein T is —CN, C₁₋₄-alkyl-S(═O)₂—CH₂—,C₁₋₄-alkyl-S(═O)₂—, R^(NT1)R^(NT2)N—S(═O)₂—, R^(NT1)R^(NT2)N—C(═O)—,C₁₋₄-alkyl-S(═O)₂—(R^(N))N—, or R^(NT1)R^(NT2)N—.
 8. The compoundaccording to claim 1, wherein R^(C) is Cl, C₁₋₄-alkyl, F₃C—,C₃₋₄-cycloalkyl, or C₁₋₃-alkyl-O—.
 9. The compound according to claim 3,wherein R^(C) is Cl, C₁₋₄-alkyl, F₃C—, C₃₋₄-cycloalkyl, orC₁₋₃-alkyl-O—.
 10. The compound according to claim 4, wherein R^(C) isCl, C₁₋₄-alkyl, F₃C—, C₃₋₄-cycloalkyl, or C₁₋₃-alkyl-O—.
 11. Thecompound according to claim 5, wherein R^(C) is Cl, C₁₋₄-alkyl, F₃C—,C₃₋₄-cycloalkyl, or C₁₋₃-alkyl-O—.
 12. The compound according to claim1, wherein: R¹ is selected from the group consisting of: a) a groupselected from:

 wherein each ring is optionally substituted with one substituent R^(C)and R^(C) is Cl, C₁₋₄-alkyl, F₃C—, C₃₋₄-cycloalkyl, or C₁₋₃-alkyl-O—, b)a group selected from:

 wherein each alkyl residue is optionally substituted with one or morefluorine atoms, and c) a group selected from

R² is H; and A is selected from the group consisting of:

 wherein T is NC—, C₁₋₄-alkyl-S(═O)₂—CH₂—, C₁₋₄-alkyl-S(═O)₂—,R^(NT1)R^(NT2)N—C(═O)—, or C₁₋₄-alkyl-S(═O)₂—NH—, and optionallyadditionally substituted with one or two F atoms, and

or a pharmaceutically acceptable salt thereof.
 13. The compoundaccording to claim 1, wherein: R¹ is selected from the group consistingof:

 wherein each ring is optionally substituted with one substituent R^(C)and R^(C) is Cl, C₁₋₄-alkyl, F₃C—, C₃₋₄-cycloalkyl, or C₁₋₃-alkyl-O—;

 wherein each alkyl residue is optionally substituted with one or morefluorine atoms; and

R² is H; and A is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 14. A pharmaceuticalcomposition comprising an effective amount of the compound according toclaim 1 and an inert carrier or diluent.
 15. A method for treatingdiabetes in a patient in need thereof, the method comprisingadministering to the patient a pharmaceutically effective amount of thecompound according to claim 1.